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As fewer preterm infants are managed with an endotracheal tube in early life, the usual conduit for surfactant delivery is lacking. With this approach has come a dilemma regarding how and when to deliver surfactant to those showing features of surfactant-deficient respiratory distress syndrome (RDS).
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Brief intubation solely for surfactant delivery has been widely practiced but has disadvantages, not the least of which is difficulty with extubation.
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A number of less invasive approaches to delivering surfactant have been used in preterm infants with RDS, including aerosolization, pharyngeal instillation, laryngeal mask administration, and brief tracheal catheterization.
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Most experience has been gained with the approach of surfactant delivery using a thin catheter briefly inserted through the vocal cords; this method has found its way into clinical practice.
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Six randomized controlled trials of surfactant administration via a thin catheter have been reported to date, with heterogeneity with regard to the settings in which the studies were conducted and many aspects of trial design.
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Pooled data from these trials suggest that surfactant delivery via a thin catheter has advantages over delivery via an endotracheal tube, with improvement in survival free of bronchopulmonary dysplasia and reduction in the need for mechanical ventilation in the first 72 hours of life.
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The question of whether a preterm infant whose condition is stable with continuous positive airway pressure (CPAP) with early signs of RDS should receive surfactant via a thin catheter or simply continue CPAP has yet to be answered with certainty.
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Circumstantial evidence suggests that delivery of surfactant to a spontaneously breathing infant being treated with CPAP is better distributed within the lung than when an equivalent dose is given via an endotracheal tube with the aid of positive-pressure ventilation. Further laboratory and clinical studies are needed to confirm this.
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Application of surfactant therapy via a thin catheter needs to be considered as part of a less invasive approach to respiratory support in preterm infants, taking account of gestation, age, and apparent severity of RDS.
Acknowledgment
As chief investigator of the OPTIMIST-A trial (NCT02140580), the author has received support from the Royal Hobart Hospital Research Foundation, the Australian National Health and Medical Research Council (grant No. 1049114), and in-kind support from Chiesi Farmaceutici S.p.A.
In surveying the well-chronicled history of respiratory management for the preterm infant with respiratory distress syndrome (RDS), there is the strong impression of having come full circle. The allure of continuous positive airway pressure (CPAP), announced with fanfare half a century ago as a means of overcoming the symptomatology of RDS in the pre-surfactant era, appeared for the most part to lose favor in the 1970s. The landscape was then dominated by intubation and mechanical ventilation, only for CPAP to be gradually rediscovered and finally reembraced as the results and meta-analyses of large clinical trials became known. Similarly, not long after its advent into clinical practice, exogenous surfactant therapy became universal and was used early, repeatedly, and certainly to good effect, in dealing with the scourge of RDS and its complications. Now, as more infants avoid intubation at the beginning of life—and thus lose the usual conduit for surfactant instillation—there is the appreciation that many infants with RDS can be successfully supported without a dose of surfactant, and the routine use of this is once indispensable drug is being questioned.
In relation to the use of CPAP, the rhetoric still remains well ahead of the practice, particularly for the smallest infants who appear to have the most to gain from a lung-protective approach to respiratory support. Well into the 21st century, the majority of infants born before 29 weeks’ gestation are still intubated routinely at the beginning of life. For many neonatologists, intubation continues to bring the certainty of the infant’s lungs being ventilated even when apneic and the timely administration of a dose of surfactant, the enduring security blanket in treating RDS. The hesitation to apply CPAP more liberally from the outset is in part fueled by the appreciation that for some infants with CPAP as initial treatment, this modality fails to provide enough support, with subsequent resorting to intubation followed by a dose of surfactant given at a later than ideal time. This pathway is known from both cohort and population-based studies to be associated with adverse outcomes, including a higher incidence of pneumothorax, bronchopulmonary dysplasia (BPD), and severe intraventricular hemorrhage (IVH). A dilemma thus exists in the management of preterm infants with RDS—should they be intubated early in life to be given a dose of surfactant or managed by CPAP to avoid the pitfalls of ventilation and the risk of ventilator-induced lung injury?
Administration of Surfactant to Infants Treated by CPAP
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. Whereas 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, several 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 draws on 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 numerous areas of uncertainty in this rapidly changing field.
Techniques of Surfactant Administration Without an Endotracheal Tube
The long-standing ingenuity of neonatologists has led to a multiplicity of methods for delivery of exogenous surfactant to the lung without using an endotracheal tube (ETT). In some cases, these methods are far from new but have been rediscovered and reapplied as more infants avoid intubation in early life. Table 12.1 documents the full range of reported techniques, which are described in further detail in the following sections.
| Technique | First Report(s) | Equipment Used |
|---|---|---|
| Aerosolization | Robillard et al. (1964), Chu et al. (1967) | Variety of aerosolization devices |
| Pharyngeal instillation | Ten Centre Study Group (1987) | Instillation catheter |
| Laryngeal mask administration | Brimacombe et al. (2004) | Laryngeal mask airway, size 1 |
| Tracheal catheterization | Verder et al. (1992) | Laryngoscope, variety of thin catheters, Magill forceps (some cases), other devices for directing catheter (some cases) |
Aerosolization
Although 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 dipalmitoylphosphatidylcholine with no spreading agents). Unfortunately, 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 less than 5 μm, surfactant aerosolization for infants with RDS remains in the province of research. Results of a series of observational studies and one small clinical trial have been recently reviewed. Clinical benefits have been noted in some studies but not in others. A further clinical trial using a vibrating membrane nebulizer for surfactant aerosolization in infants between 29 and 33 weeks’ gestation reported a clinical benefit in relation to need for subsequent intubation (odds ratio 0.56, 95% confidence interval 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.
Pharyngeal Instillation of Surfactant
Although it was established several decades ago as a method of initial surfactant delivery, pharyngeal surfactant instillation shortly after birth has been largely forgotten. Kattwinkel and coworkers rediscovered the technique and applied it in preterm infants of 27 to 30 weeks’ gestational age. Most infants studied showed an improvement in oxygenation, indicative of surfactant delivery to the lung. Four required redosing after endotracheal intubation, and there were some reservations expressed by the authors about the applicability of the technique during cesarean delivery (especially using general anesthesia) and with breech presentation. Some enthusiasm for the method continues to the present day, with a recent report of pharyngeal surfactant administration in extremely preterm infants (<25 weeks’ gestation), suggesting better transition and lesser need for intubation compared with nonrandomized controls. A further randomized controlled trial (RCT) examining the efficacy of delivery room pharyngeal surfactant administration is underway in infants 28 weeks’ gestation or less (the POPART [Prophylactic Oropharyngeal Surfactant For Preterm Infants: A Randomised Trial, EudraCT 2016-004198-41). For such infants, administration of surfactant with the first inflations of the lung may have a marked physiologic effect in lung fluid clearance and aeration, beyond any effect on replenishment of the surfactant pool. For infants beyond 28 weeks’ gestation, 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. In a group of 8 infants of 28 to 35 weeks’ gestational age, Trevisanuto et al. reported the placement of an LMA without sedation, through which surfactant was administered by rapid bolus, followed by positive-pressure inflations. Improvement in oxygenation was noted in all cases; two infants were subsequently intubated, including one with a pneumothorax. More recently, interest in surfactant delivery by LMA has burgeoned, with two RCTs comparing LMA administration with surfactant therapy after intubation, and two others in which the comparator group was continuation of CPAP. All studies concentrate on infants at 28 weeks’ gestation and older, this being the lower limit of gestation at which the smallest LMA (size 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 postprocedure 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 ∼20% might be expected in infants of 28 weeks’ gestation or older, both with ETT administration or by a thin catheter. Ultimately, the applicability of LMA surfactant delivery will depend on (1) the results of head-to-head comparisons with other forms of less invasive surfactant administration and (2) the willingness of clinicians to gain familiarity with LMA placement, a procedure that is otherwise uncommon in most neonatal intensive care nurseries (NICUs).
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 supported with CPAP and 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 intensified since. Given the wide experience and clinical applicability of this technique, the remainder of this chapter focuses on this approach to surfactant delivery.
Surfactant Administration Via Brief Tracheal Catheterization
Methods of Surfactant Delivery Via a Thin Catheter
Table 12.2 shows reported techniques for surfactant delivery via thin catheter. Some techniques involve the use of instrumentation to aid passage of the catheter tip through the vocal cords (e.g. Magill forceps), yet others use no internal guide and rely on the skill of the clinician to direct the catheter into the trachea. A semirigid rather than flexible catheter has generally been used for this latter approach, with the exception of the RCT by Kanmaz et al., in which the trachea was catheterized with a flexible catheter without Magill forceps. Beyond these original reports, a wide range of different catheters has now been used for surfactant delivery, including umbilical, suction, and urethral catheters, inserted by both oral and nasal routes.
| Method, Reference | Catheter Type | Guidance Through Vocal Cords |
|---|---|---|
| Cologne method (LISA) | Flexible nasogastric tube | Magill forceps |
| Take Care method | Flexible nasogastric tube | No forceps |
| Hobart method | Semirigid vascular catheter | No forceps |
| SONSURE | Flexible nasogastric tube | Magill forceps |
| QuickSF | Soft catheter | Intrapharyngeal guide |
Depth of Catheter Insertion
As with surfactant instillation via an ETT, the position of the catheter tip in the trachea is critically important; surfactant reflux into the pharynx or surfactant delivery preferentially into the right lung are the potential consequences of an overly shallow or deep tip position, respectively. Reported catheter insertion depth has been 1 to 2 cm beyond the 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 the vocal cords at less than 27 weeks’ gestation and 2 cm for more mature infants has been made. Note that for many catheters (vascular catheter, feeding tube) a mark must 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-center and multicenter experiences with this approach to surfactant delivery have now been reported. The experience of surfactant delivery via a thin catheter runs to several thousand infants, and information from these studies is used in later text sections. Readers are referred to recent reviews for discussion of individual studies.
Clinical Trials of Surfactant Administration Via Tracheal Catheterization
The key features of the six clinical trials in which the efficacy of surfactant delivery via tracheal catheterization has been evaluated in preterm infants with RDS are shown in Tables 12.3 and 12.4 , with commentary on each trial and an overall summation in the next sections.
| Trial Name, Author, (Year) | Gestation Range (Weeks) | Time of Entry | Entry Criteria | Intervention | Blinding | Surfactant Dose, Type | Control Group | Primary Outcome |
|---|---|---|---|---|---|---|---|---|
| AMV Göpel et al. (2011) | 26–28 | <12 h | Fi o 2 ≥ 0.30 | Cologne method | No | 100 mg/kg, Curosurf/Survanta/ Alveofact | Continue with CPAP | Intubation on day 2 or 3 |
| Take Care Kanmaz et al. (2013) | <32 | <2 h | Fi o 2 ≥ 0.40 | Take Care method | No | 100 mg/kg, Curosurf | INSURE without sedation | Intubation <72 h |
| Mirnia et al. (2013) | 27–32 | NS | Fi o 2 ≥ 0.30 | Cologne method | No | 200 mg/kg, Curosurf | INSURE without sedation | NS |
| Bao et al. (2015) | 28–32 | <2 h | Fi o 2 ≥ 0.30 (28–29 weeks), ≥0.35 (30–32 weeks) with RDS | Hobart method | No | 200 mg/kg, Curosurf | INSURE without sedation | Intubation <72 h |
| Mohammadizadeh et al. (2015) | <35 | <2 h | Fi o 2 ≥ 0.30 and/or Silverman score ≥ 5 | Cologne method | No | 200 mg/kg, Curosurf | INSURE without sedation | Intubation <72 h |
| NINSAPP Kribs et al. (2015) | 23–26 | 10–120 min | Fi o 2 ≥ 0.30 and/or Silverman score ≥ 5 | Cologne method | No | Median 200 mg/kg, Curosurf | Intubation, ventilation, surfactant therapy | Survival without BPD |
| Trial Name Author (Year) | Group | Total No. | Actual Gestation (Weeks) | No. at 29–32 Weeks | Fi o 2 at Enrollment | Result re Primary Outcome (%) | Intubated in First 72 h (%) | Pneumothorax (%) | BPD in Survivors (%) | Death (%) | Death or BPD (%) |
|---|---|---|---|---|---|---|---|---|---|---|---|
| AMV trial Göpel et al. (2011) | CPAP | 112 | 27.5 | 0 | 0.45 | 46 | 46 | 7 | 13 | 5 | 15 |
| Surfactant via catheter | 108 | 27.6 | 0 | 0.4 | 28 a | 28 a | 4 | 8 | 7 | 14 | |
| Take Care Kanmaz et al. (2013) | INSURE | 100 | 28.3 | 45 | 0.55 | 45 | 45 | 10 | 20 | 13 | 32 |
| Surfactant via catheter | 100 | 28 | 41 | 0.6 | 30 a | 30 a | 7 | 10 a | 16 | 22 | |
| Mirnia et al. (2013) | INSURE | 70 | 29.6 | 44 | 0.42 | 22 | 6 | 7 | 16 | 23 | |
| Surfactant via catheter | 66 | 29.6 | 44 | 0.43 | 19 | 5 | 8 | 3 a | 11 | ||
| Bao et al. (2015) | INSURE | 43 | 29.3 | 25 | 0.43 | 23 | 23 | 7 | 14 | 0 | 14 |
| Surfactant via catheter | 47 | 29.1 | 25 | 0.43 | 17 | 17 | 9 | 13 | 2 | 15 | |
| Mohammadizadeh et al. (2015) | INSURE | 19 | 31 | 17 | NS | 16 | 16 | 21 | 16 | 37 | |
| Surfactant via catheter | 19 | 30 | 17 | NS | 11 | 11 | 16 | 5 | 21 | ||
| NINSAPP Kribs et al. (2015) | Intubated | 104 | 25.2 | 0 | NS | 59 | 100 | 13 | 30 | 12 | 41 |
| Surfactant via catheter | 107 | 25.3 | 0 | NS | 67 | ∼40–50 | 5 a | 25 | 9 | 33 | |
| Total No. | 895 | 258 |
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