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Exogenous surfactant therapy in 2013: what is next? who, when and how should we treat newborn infants in the future?

BMC Pediatrics volume 13, Article number: 165 (2013) Cite this article

Abstract

Background

Surfactant therapy is one of the few treatments that have dramatically changed clinical practice in neonatology. In addition to respiratory distress syndrome (RDS), surfactant deficiency is observed in many other clinical situations in term and preterm infants, raising several questions regarding the use of surfactant therapy.

Objectives

This review focuses on several points of interest, including some controversial or confusing topics being faced by clinicians together with emerging or innovative concepts and techniques, according to the state of the art and the published literature as of 2013. Surfactant therapy has primarily focused on RDS in the preterm newborn. However, whether this treatment would be of benefit to a more heterogeneous population of infants with lung diseases other than RDS needs to be determined. Early trials have highlighted the benefits of prophylactic surfactant administration to newborns judged to be at risk of developing RDS. In preterm newborns that have undergone prenatal lung maturation with steroids and early treatment with continuous positive airway pressure (CPAP), the criteria for surfactant administration, including the optimal time and the severity of RDS, are still under discussion. Tracheal intubation is no longer systematically done for surfactant administration to newborns. Alternative modes of surfactant administration, including minimally-invasive and aerosolized delivery, could thus allow this treatment to be used in cases of RDS in unstable preterm newborns, in whom the tracheal intubation procedure still poses an ethical and medical challenge.

Conclusion

The optimization of the uses and methods of surfactant administration will be one of the most important challenges in neonatal intensive care in the years to come.

Peer Review reports

Since the first successful studty by G. Enhoring and B. Robertson in 1972 demonstrating the effectiveness of natural lung surfactant administration in an immature rabbit model of respiratory distress syndrome (RDS) [1], many clinical studies have been carried out using synthetic or natural surfactant. Surfactant therapy is one of the few treatments that decreases overall mortality in preterm newborns with RDS, and has significantly changed clinical practice in neonatology. However, surfactant deficiency is also observed in many clinical situations other than RDS in term and preterm infants. This review focuses on the most controversial and confusing topics being faced by clinicians today, and emerging or innovative concepts and techniques regarding the use of surfactant therapy in respiratory management.

A systematic PubMed search up to January 2013 was undertaken to identify manuscripts addressing the following three specific questions:

  1. 1.

    Which infants should we treat with exogenous surfactant therapy?

  2. 2.

    When should preterm infants with RDS be treated with exogenous surfactant?

  3. 3.

    How should preterm infants with RDS be treated with exogenous surfactant?

Which infants should we treat with exogenous surfactant therapy?

Surfactant therapy for primary surfactant deficiency

Surfactant therapy for RDS in the preterm newborn

Surfactant synthesis starts early in fetal life and increases with gestational age. Over the last 10 years, meta-analyses have confirmed that exogenous surfactant treatment decreases overall morbidity and mortality in preterm newborns with RDS [2, 3]. Both animal and human studies have demonstrated that early administration of surfactant is more effective than later rescue surfactant treatment because of better surfactant distribution and avoidance of ventilator-induced lung injury [4, 5]. As of today, the questions that remain concerning surfactant therapy in preterm infants with RDS revolve around the identification of infants requiring surfactant, and the delivery method and dosage of surfactant administration. Indeed, emergency tracheal intubation in the delivery room for prophylactic or early surfactant administration raises ethical issues regarding pain management and the side effects induced by the procedure [6–8]. Other aspects of surfactant delivery, including the volume of surfactant administered, the rapidity of administration, drug viscosity and delivery rate, are also of interest. Finally, potential methods for the selection of infants with surfactant deficiency despite antenatal exposure to steroids include the stable microbubble test [9] and the click test, leading to earlier administration and reduced surfactant use [10].

Exogenous surfactant therapy for newborns of diabetic mothers

Epidemiological studies have shown that the risk of RDS is 5.6 times greater in newborn infants of diabetic mothers than in infants of non-diabetic mothers [11]. Although the strict management of maternal diabetes has reduced the incidence of RDS in very preterm infants of mothers with pregestational and gestational diabetes mellitus, pathophysiological data suggest that lung maturation is delayed in this population. In addition, although some studies show normal levels of disaturated phosphatidylcholine (DSPC), the main component of surfactant, in the amniotic fluid of diabetic pregnant women [12], others have revealed a decrease in DSPC levels in these pregnancies [13]. Even though these epidemiological and pathophysiological data suggest that the use of surfactant therapy would be beneficial in newborns born to diabetic mothers, no prospective study has as yet been performed in this population.

Newborns with genetic mutations in surfactant proteins

Lung diseases associated with surfactant metabolism dysfunctions represent a heterogeneous group of rare disorders [14], usually with poor prognosis and weak or transient effects of mechanical ventilation or exogenous surfactant therapy [15]. These conditions are rarely known before birth unless there has been a previously affected infant. The inherited deficiency of pulmonary surfactant B protein (SP-B) was first described in term newborns with RDS in 1993 [16]. Since then, other genetic mutations in surfactant proteins have been described, of which some induce RDS in newborns within the first few days of life while others result in lung diseases in older infants. These include mutations of the surfactant protein C (SP-C) gene [17], mutations in proteins required for surfactant synthesis, such as the ATP-binding cassette transporter, subfamily A, member 3 (ABCA3) [18] or the NK2 homeobox protein NKX2-1, a critical regulator of the transcription of SP-B and SP-C [19]. Steroids, hydroxychloroquine and azithromycin have been proposed in older patients, but little information is available to assess the benefit/risk ratio of these treatments.

Surfactant therapy for secondary surfactant deficiency

Various clinical situations such as pulmonary haemorrhage, meconium aspiration syndrome (MAS), pulmonary infection and atelectasis have been shown to liberate inflammatory mediators that damage type II pneumocytes and inactivate surfactant [20, 21]. Surfactant replacement therapy could thus be useful as a supporting treatment in this population of newborns with secondary or transient surfactant deficiency.

Surfactant therapy in term and near-term newborns with acute respiratory distress syndrome (ARDS)

The incidence of ARDS requiring mechanical ventilation in term and near-term newborns is 7.2/1000 live births, and 30% of newborns requiring mechanical ventilation in the neonatal intensive care unit (NICU) are low birth-weight infants [22]. The incidence of ARDS decreases from 10.5% (390/3700) for infants born at 34 weeks of gestation to 0.3% (140/41,764) at 38 weeks [23]. The incidence of respiratory morbidity is significantly higher in newborns delivered by caesarean section before the onset of labour (35.5/1000) than in those delivered by caesarean section during labour (12.2/1000) or in vaginal births (5.3/1000) [24]. Even among deliveries by caesarean section before the onset of labour, a significant reduction in the incidence of ARDS could be obtained if elective caesarean section is performed after the 39th week of gestation [24, 25]. Even if the overall incidence of ARDS seems low in term and near-term newborns, these still constitute a high-risk population with significant neonatal mortality and morbidity including air leaks, severe hypoxaemia, persistent pulmonary hypertension and bronchopulmonary dysplasia [26]. The mechanisms leading to ARDS in term or near-term newborns involve delayed lung liquid clearance and insufficient surfactant production. Similarly, term infants with transient tachypnea of the newborn have low lamellar body counts associated with decreased surfactant function, suggesting that prolonged disease is associated with surfactant abnormalities [27].

Surfactant therapy for newborns with pulmonary haemorrhage

Experimental data suggest that the molecular components involved in pulmonary haemorrhage can biophysically inactivate endogenous lung surfactant, whereas exogenous surfactant replacement is capable of reversing this process even in the continued presence of inhibitor molecules [28, 29]. In two clinical studies, whose control groups were not comparable, the mean oxygenation index improved in preterm and term infants who received surfactant following clinically significant pulmonary haemorrhage, with no deterioration in the condition of any patient [30, 31]. Case reports have also noted the successful use of surfactant treatment after idiopathic [32] or iatrogenic pulmonary haemorrhage [33]. However, a recent Cochrane meta-analysis found no any randomized or quasi-randomized trials evaluating the effects of surfactant in pulmonary haemorrhage in neonates [34], suggesting the need for such trials.

Surfactant therapy in meconium aspiration syndrome (MAS)

MAS is characterized by the early onset of respiratory distress in meconium-stained infants, resulting in high pulmonary morbidity and mortality [35, 36]. The pathophysiology of MAS includes airway obstruction [37, 38], alveolar inflammation [39] and surfactant inhibition [40, 41]. Over the last 10 years, cohort studies assessing the use of treatments such as High-Frequency Oscillatory Ventilation (HFOV) or inhaled Nitric Oxide (iNO) in MAS have not revealed any decrease in the duration of ventilation or oxygen therapy [42, 43].

Surfactant treatment has been proposed in MAS, either as a bolus treatment or surfactant lavage. In one meta-analysis, bolus surfactant treatment for MAS decreased the need for extracorporeal membrane oxygenation (ECMO) (NNT=6), but had no statistically significant effect on mortality, duration of assisted ventilation, duration of supplemental oxygen, pneumothorax, pulmonary interstitial emphysema, air leaks, chronic lung disease, need for oxygen at discharge or intraventricular haemorrhage [44]. Surfactant lavage has been performed in several animal and human studies, with an optimal total lavage fluid volume of 15 to 30 mL/kg [35, 45, 46]. The surfactant was diluted in these studies in physiological saline to obtain a final phospholipid concentration of 5 mg/mL [47]. In a recent meta-analysis of surfactant lavage, Hahn et al. state that lung lavage with diluted surfactant may be beneficial to infants with MAS, but additional controlled clinical trials of lavage therapy should be conducted to confirm this effect, to refine the method of lavage, and to compare lavage with other approaches [48]. In a study of newborn lambs with respiratory failure and pulmonary hypertension induced by MAS, gas exchange and lung compliance were improved by lung lavage with dilute surfactant but not by bolus treatment [49]. Given these results, it is safe to conclude that surfactant treatment, either as a bolus or diluted for lung lavage, would decrease the need for ECMO in human newborns with MAS. Furthermore, in infants with MAS, if ECMO is not available, surfactant administration may reduce the severity of respiratory illness and decrease the number of infants with progressive respiratory failure requiring support with ECMO. Larger clinical trials are necessary to confirm that surfactant may be an effective treatment for the aspiration of several biological fluids in addition to meconium, including blood, vernix and amniotic fluid.

Surfactant therapy for impaired lung alveolarization

Both congenital and acquired lung growth impairments result in a decrease in lung alveolarization, type II pneumocyte counts and surfactant production [50–52], suggesting a potential benefit from surfactant replacement therapy.

Exogenous surfactant therapy for congenital diaphragmatic hernia (CDH)

Newborns with CDH display pulmonary hypoplasia with persistent pulmonary hypertension (PPH), resulting in a high incidence of respiratory morbidity and mortality [53, 54]. Animal models of CDH have revealed a deficient surfactant system [50, 55, 56]. In human studies, Boucherat et al. have shown that CDH does not impair storage in fetuses [57]. CDH lungs exhibit no trend towards a decrease in content or a delay in developmental changes for any of the surfactant components or surfactant maturation factors studied. Data from cohorts of newborns with a prenatal diagnosis of isolated CDH do not show any benefit associated with surfactant therapy [53]. However, surfactant phosphatidylcholine synthesis is decreased in newborns with CDH who require ECMO after birth [58]. A plausible explanation for the difference in surfactant synthesis is that CDH infants who require ECMO have more severe pulmonary hypoplasia compared to CDH infants who do not require ECMO. Systematic surfactant therapy can thus not be recommended for term newborns with a prenatal diagnosis of isolated CDH. Whether surfactant therapy is beneficial or not in preterm or late preterm newborns with CDH who require ECMO should be evaluated in randomized trials that also take into account the severity of the underlying lung hypoplasia and gestational age at delivery.

Late surfactant therapy for chronically ventilated preterm infants

In spite of early exogenous surfactant treatment, extremely low birth weight infants can develop persistent respiratory failure during the first weeks of life, leading to bronchopulmonary dysplasia (BPD) and alveolarization defects [52]. Surfactant proteins are involved in the pulmonary host defence and response to lung injury. The synthesis of surfactant proteins has been found to be decreased in animal models of BPD [59]. Preterm infants requiring chronic ventilation after 7 days of life also present dysfunctional surfactant proteins [60].

Studies evaluating the effects of surfactant administration in chronically ventilated preterm infants have demonstrated a short-term beneficial effect on the fraction of inspired oxygen (FiO2) and the respiratory distress severity score at 48 and 72 hours [61]. However, the sole study to evaluate the effect of late surfactant treatment on the incidence of BPD or mortality has reported trends toward lower morbidity/mortality only in infants who received high dose of lucinactant [62].

When should preterm infants with rds be treated with exogenous surfactant?

The optimal timing (prophylactic or selective) for the administration of surfactant to preterm infants with RDS has been assessed by many studies, and discussed in recent reviews [63]. On the basis of these studies, various guidelines have been elaborated by national expert committees in accordance with current practice and conclusions drawn from recent large trials of CPAP.

Prophylactic vs. selective surfactant treatment

Rojas-Reyes et al. [5] have carried out a meta-analysis comparing the effectiveness of prophylactic vs. selective exogenous surfactant administration in preventing morbidity and mortality in very preterm infants below 30–32 weeks gestational age (GA). Prophylactic administration decreases the incidence of pneumothorax, pulmonary interstitial emphysema, neonatal mortality and BPD or death to a greater extent than selective treatment. However, several limitations of this meta-analysis should be noted: (i) the range of gestational ages studied was large, (ii) the exogenous surfactant used was natural but was different in each study, and (iii) the timing of selective surfactant administration was very different among the studies, from 1 hour to 24 hours after birth. In addition, the beneficial effect of prophylactic surfactant on neonatal mortality or air-leak syndromes was only seen in infants not routinely subjected to CPAP. Finally, the increasing use of antenatal betamethasone in the current era could be an explanation for the lower impact of prophylactic surfactant.

Early vs. late surfactant treatment

The benefits of early (< 2 hours) and delayed (> 2 hours) surfactant administration have been recently reviewed [4] in a meta-analysis of six randomized controlled trials (RCTs), consisting of two trials with synthetic (Exosurf Neonatal) and four using animal-derived surfactant preparations [64–69]. According to this meta-analysis, early selective surfactant administration to infants with RDS requiring assisted ventilation leads to a decreased risk of acute pulmonary injury (decreased risk of pneumothorax and pulmonary interstitial emphysema) and a decreased risk of neonatal mortality and chronic lung disease, compared to delaying treatment of such infants until they develop worsening RDS.

More recently, two new RCTs have demonstrated that routine early surfactant administration within 2 hours of life:

  • reduces the need for mechanical ventilation in the first week of life among preterm infants with RDS on nasal CPAP, born between 28 and 32 weeks GA [70],

  • decreases intra-ventricular haemorrhage (≥ grade III) and pneumothorax rates but does not have any effect on BPD when compared to delayed surfactant administration [71].

National guidelines for exogenous surfactant administration

Table 1 summarizes national recommendations for surfactant prophylactic use. The British Association of Perinatal Medicine recommended in 1999 that very preterm infants, born before 32 weeks GA be treated with exogenous surfactant at birth only if they needed intubation, and that all very preterm infants below 29 GA be intubated for the administration of exogenous surfactant [72]. More recently, in 2008, the American Academy of Pediatrics Committee on the Fetus and Newborn has recommended using surfactant in infants with RDS as soon as possible after intubation, irrespective of exposure to antenatal steroids or gestational age. They have also recommended that prophylactic surfactant treatment be administered to extremely preterm infants (< 28 weeks GA) at high risk of RDS, especially infants who have not been exposed to antenatal steroids [73]. The Canadian Paediatric society has advocated that intubated infants with RDS receive exogenous surfactant therapy, and that infants at significant risk of RDS receive prophylactic surfactant treatment as soon as they are stable, within a few minutes of intubation [74]. The consensus guidelines developed by European experts in neonatology recommend prophylactic surfactant administration to all extremely preterm infants born at less than 26 weeks GA and to all preterm infants with RDS who require intubation for stabilization. In addition, they recommend that early rescue surfactant therapy be administrated to untreated preterm infants with RDS [75]. In a recent update of European consensus guidelines on the management of neonatal respiratory distress syndrome in preterm infants, the experts state that the best preparation, optimal dose and timing of surfactant administration at different gestational ages is not completely clear. In addition, the use of very early CPAP has altered the indications for prophylactic surfactant administration [76].

Table 1 International guidelines for RDS treatment
Full size table

A European survey conducted in 2011 has analysed the incorporation of guidelines for surfactant therapy into clinical practice in 173 NICUs across 21 European countries [77]. Only 39% of the NICUs used prophylactic treatment. Twenty-three % of preterm infants received their first surfactant dose within the first 15 minutes after birth, while 28% of them received it after 2 hours of life. A gestational age of less than 28 weeks and a birth weight of less than 1000 g were used as criteria for prophylactic treatment in most of NICUs. Eighty eight % used a median FiO2 of greater than 0.40 as the indication for rescue surfactant treatment, at a median time of 2 hour after birth.

CPAP vs. intubation for exogenous surfactant infusion in the age of antenatal corticosteroids

There is increasing evidence to suggest that CPAP immediately after birth is a reasonable alternative to systematic intubation for surfactant administration to preterm infants. Recent trials on this topic are summarized in Table 2.

Table 2 Recent studies concerning CPAP and surfactant administration
Full size table

Morley et al. [78] demonstrated, in the COIN trial, that early nasal CPAP did not reduce the rate of death or BPD, but the need for intubation and use of surfactant were halved (38% vs. 77%; p<0.001) in extremely preterm infants. This study suggests that starting respiratory support with CPAP did not adversely affect infants even if the incidence of pneumothorax was increased in the CPAP group when compared with the intubation group (9% vs. 3%; p<0.001). Rojas et al. [79] conducted a trial showing that an “intubation-very early surfactant administration-extubation” sequence improved outcome in very preterm infants by decreasing the need for mechanical ventilation and the incidence of air-leak syndromes, when compared with CPAP therapy alone. In the CURPAP trial [80], prophylactic surfactant administration to very preterm infants was not superior to CPAP or early selective surfactant treatment in reducing the need for mechanical ventilation, pneumothorax, BPD or mortality.

In the SUPPORT trial [81], the authors randomized 1316 infants born at 24–27 weeks GA into two groups: a CPAP group and a surfactant group (intubation and prophylactic surfactant administration). The primary outcome (death or BPD at 36 weeks) did not differ significantly between the two groups. In addition, a high proportion (46%) of infants assigned to the “initial CPAP” group still ended up being intubated and receiving surfactant. Dunn et al. [82] compared 3 strategies for initial respiratory management in infants born between 26 and 29 weeks GA: 1) prophylactic surfactant administration followed by mechanical ventilation, 2) intubation-early surfactant use-extubation and 3) initial CPAP with selective surfactant treatment. The incidence of death or BPD at 36 weeks was similar in the 3 groups. No significant differences were found at 18 to 22 months of corrected age with regard to the composite outcome of death or neurodevelopmental impairment between extremely premature infants randomly assigned to early CPAP or early surfactant administration and to a lower or higher target range of oxygen saturation [83]. These controlled studies demonstrate that early CPAP use safely reduces the number of infants intubated and treated with surfactant compared to prophylactic surfactant administration or the intubation-surfactant-extubation approach. Unfortunately, neither the SUPPORT nor the COIN trial helps to identify infants at birth who, if initially ventilated using CPAP, will subsequently require intubation and ventilation.

Prophylactic vs. selective surfactant administration in the age of antenatal corticosteroids and CPAP

Rojas-Reyes et al. [5] have recently updated a meta-analysis comparing the effects of prophylactic surfactant with selective surfactant treatment. The benefits of the prophylactic surfactant strategy demonstrated by the first meta-analysis are not confirmed by this updated meta-analysis. Recent large trials that reflect the current increase in antenatal corticosteroid administration and routine post-delivery stabilization on CPAP also do not support these benefits.

In summary, early selective surfactant treatment in preterm infants with RDS is more effective than delayed selective surfactant use in reducing neonatal mortality, pneumothorax, and BPD at 36 weeks. Prophylactic treatment also decreases the incidence of pneumothorax, pulmonary interstitial emphysema, BPD and neonatal mortality when compared with delayed selective treatment. However, prophylactic surfactant treatment is not superior to initial respiratory support with CPAP followed by selective surfactant treatment later on in reducing the need for mechanical ventilation, pneumothorax and BPD or mortality in the era of antenatal corticosteroids and CPAP.

How should preterm infants with rds be treated with exogenous surfactant: InSurE or MIST?

The “InSurE” strategy

The InSurE approach is a strategy in which surfactant is administered during brief intubation followed by immediate extubation and nasal respiratory support. This strategy has been shown in earlier RCTs to halve the need for subsequent mechanical ventilation. More recently, Bhandari et al. have demonstrated that the InSurE strategy is associated with a significantly lower incidence of BPD or death (20% vs. 52%; p=0.03) [84].

A Cochrane review updated in 2007 has compared InSurE with later selective surfactant use. The InSurE strategy is associated with a significantly lower incidence of mechanical ventilation and a trend towards a decrease in BPD and air-leak syndromes [85]. Rojas et al. evaluated very early surfactant administration with early CPAP in very preterm infants [79]. In the InSurE group, the need for mechanical ventilation was significantly lower and air-leak syndromes were less frequent, but the decrease in the incidence of BPD did not reach statistical significance. Dani et al. have identified the clinical characteristics that could predict the success or failure of InSurE in infants [86]. Gestational age, birth weight and the need for oxygen are independent risk factors for InSurE failure in infants. Kirsten et al. have also reported in a recent observational study that early neonatal outcome in extremely immature infants may be improved by the administration of antenatal steroids as well as the InSurE strategy [87].

Taken together, these various studies demonstrate that InSurE is a safe and effective method that reduces the need for mechanical ventilation, the duration of respiratory support and the need for surfactant replacement in preterm infants with RDS. It may also reduce the rate of BPD and air-leak syndromes, but limited data are available regarding cerebral oxygenation and the potential risk of brain damage. This strategy needs to be individually tailored in accordance with the infant’s maturity and general clinical condition, the use of antenatal steroid treatment, the severity of RDS and certain practical considerations affecting the NICU.

Emerging techniques for surfactant administration

Considering the risks associated with the use of an endotracheal tube (usually associated with premedication that contributes to a delay in extubation), Minimally-Invasive Surfactant Therapy (MIST) and Non-Invasive Surfactant Therapy (NIST) are emerging methods for surfactant administration without the need for positive-pressure mechanical ventilation (Table 3) [88].

Table 3 Emerging approaches to surfactant administration
Full size table

Should surfactant always be administered through an endotracheal tube?

Intrapartum pharyngeal instillation

An initial multicenter trial tested surfactant administration to the posterior pharynx immediately following birth, before the first inspiration of air [89]. In this trial, the solution was not administered under CPAP and many of the subjects also received surfactant through an endotracheal tube. More recently, 23 neonates born between 27 and 30 weeks GA were treated by surfactant instilled into the nasopharynx before the delivery of the shoulders. Thirteen of 15 babies delivered vaginally were weaned quickly to room air and required no further surfactant or tracheal intubation for RDS. Evidence from animal and observational human studies suggests that the pharyngeal instillation of surfactant before the first breath is potentially safe, feasible and effective. Well-designed trials are still needed to confirm this [90].

Laryngeal mask

The laryngeal mask airway (LMA) is a supraglottic device used to administer non-invasive pressure ventilation to adult, paediatric and neonatal patients. Trevisanuto et al. used a laryngeal mask to deliver surfactant to 8 preterm and near-term infants with RDS and a birth weight > 800 g [91], leading to an increased mean arterial/alveolar oxygen tension ratio (a/APO2) without complications. The Cochrane review cited above [90] reported no study of prophylactic surfactant administration using an LMA. The Cochrane experts concluded that there was some evidence that selective surfactant administration through an LMA to preterm infants > 1200 g with established RDS reduced oxygen requirement in the short term, although the LMA technique needed to be further evaluated in clinical trials, including those dedicated to investigating the size of the LMA used according to gestational age.

Feeding and vascular catheter

An alternative route for surfactant administration in spontaneously breathing preterm infants on CPAP consists of introducing surfactant via a thin endotracheal catheter under laryngoscopy. The tube is inserted only for the few minutes necessary to administer surfactant. The first cases using this technique were reported by Verder et al. [92]. A recent multicentre RCT including very preterm infants has compared a standard group (CPAP, rescue intubation and surfactant treatment if needed) with an intervention group (surfactant via thin catheter) [93]. According to this non-blinded trial, the new method reduces the need for subsequent mechanical ventilation on day 2 or 3 after birth, and the duration of mechanical ventilation as well as the need for oxygen therapy at 28 days. However, the risk of death or BPD at 36 weeks does not differ between the two groups, and the trial has prompted a few methodological concerns. These findings may be of interest for infants that have received antenatal steroids.

The use of a more stable vascular catheter (the Hobart method) for surfactant administration allows easier placement without the use of Magill forceps [94]. A preliminary evaluation of this new technique in preterm infants showed that surfactant was successfully administered and CPAP quickly re-established, with decreasing FiO2. Transient coughing (32%) and bradycardia (44%) were noted, and 44% of patients received positive-pressure inflation. Multicentre RCTs of surfactant administration via catheterization in preterm infants on CPAP are ongoing (the OPTIMIST-A and -B trials). In active preterm infants, the placement of a catheter without sedation may be difficult and potentially traumatic. Guidelines for premedication are therefore needed to minimize this risk.

Non-Invasive Surfactant Therapy (NIST): aerosolized surfactant

Within a few years of Patrick Kennedy’s death from RDS in 1963, the first two trials reporting the use of synthetic surfactants were published [95, 96]. Both used nebulized dipalmitoyl-phosphatidylcholine, with no discernible beneficial effects. Since then, several pilot trials have been published, but it has not been possible to clearly demonstrate whether surfactant can be successfully administered via nebulization [97]. To be effective, the surfactant would have to be unaltered by the aerosolization process: i.e. capable of being delivered to distal portions of the lung, reaggregating, and maintaining its biological activity. Several animal studies have directly compared aerosolization to tracheal instillation, and reported that aerosolization can be of equal or greater effectiveness [98], whereas others have found that instillation is more effective than aerosolization [99]. An example illustrating the need for further clarity on this issue is the study by Lewis et al. [100]. In sheep, exogenous bovine lung extract surfactant was effective when instilled but ineffective when aerosolized, whereas beractant in the same animal model was more effective when aerosolized than when instilled. Aerosol delivery to the alveoli in normal lungs is maximal in the particle-size range 0.5-2.0 μm, and it is possible to generate a stable surfactant aerosol with that particle-size range from aqueous or powdered surfactant [101]. Currently, 3 types of nebulizers are available: jet nebulizers, ultrasound nebulizers and vibrating-membrane nebulizers. If aerosol delivery technology for lung surfactant could be perfected, this would clearly be a conceptually attractive alternative to instillation for clinical application. Indeed, aerosol delivery might avoid the transient endotracheal tube obstruction and resultant hypoxia and hypotension seen with bolus instillation. However, delivering aerosolized surfactant in sufficient quantities and achieving its uniform distribution throughout the alveoli of injured lungs in ventilated units is a key challenge. Whether surfactant aerosolization can be accomplished in a sufficiently effective and efficient manner to replace instillation requires further direct comparisons in animals and subsequently in human trials. A recent clinical study using aerosolized lucinactant has demonstrated the feasibility and safety of delivering this synthetic-peptide-containing surfactant to newborns with early signs of RDS [102]. Nebulized surfactant is potentially a therapeutic option to avoid the severe volutraumatic and barotraumatic effects of mechanical ventilation. However, several issues regarding cost-effectiveness, the development of nebulizer devices capable of its administration, and dosing strategies remain unresolved [103]. An open-label randomized controlled pilot study to evaluate the safety and efficacy of aerosolized porcine surfactant in the first hour of life in preterm infants with RDS (CureNeb) is ongoing in Australia. The primary outcomes evaluated are the duration of mechanical ventilation and the need for intubation.

In conclusion, surfactant administration via an endotracheal tube remains the gold standard for surfactant administration in intubated infants. However, CPAP, as the primary respiratory support technique in infants with RDS, has been shown to be at least as effective as mechanical ventilation, and newly emerging techniques for surfactant administration in non-ventilated infants are currently under investigation. The optimization of a less- or non-invasive method of surfactant administration will be one of the most important challenges in the field of surfactant therapy for RDS in the coming years.

Potential adverse effects and safety of exogenous surfactant therapy

The short-term risks of surfactant administration include bradycardia and hypoxemia during instillation, as well as blockage of the endotracheal tube [104]. The relative risk of pulmonary haemorrhage following surfactant therapy has been reported at 1.47 (95% CI: 1.05 to 2.07) in trials [105], but this adverse event is rarely reported in many of the RCTs of surfactant administration. Moreover, a recent meta-analysis that included 4 trials did not show any significant difference in the risk of pulmonary haemorrhage between prophylactic vs. selective administration of surfactant [5]. Due to the very rapid improvement in gas exchange in surfactant-treated infants, overdistension and hyperventilation with low partial pressure of carbon dioxide (PCO2) can occur. No other adverse clinical outcome has been shown to be increased by surfactant replacement. However, emerging techniques for surfactant administration may give rise to new and unexpected adverse events that must be taken into account in current and future studies.

To date, there is no evidence that there are any immunological changes of clinical concern due to bovine or porcine sources of proteins contained in natural surfactants [106].

References

  1. Enhörning G, Robertson B: Lung expansion in the premature rabbit fetus after tracheal deposition of surfactant. Pediatrics. 1972, 50: 58-66.

    PubMed  Google Scholar 

  2. Soll R, Ozek E: Prophylactic protein free synthetic surfactant for preventing morbidity and mortality in preterm infants. Cochrane Database Syst Rev. 2010, 1: CD001079

    Google Scholar 

  3. Soll RF: Prophylactic synthetic surfactant for preventing morbidity and mortality in preterm infants. Cochrane Database Syst Rev. 2000, 2: CD001079

    Google Scholar 

  4. Bahadue FL, Soll R: Early versus delayed selective surfactant treatment for neonatal respiratory distress syndrome. Cochrane Database Syst Rev. 2012, 11: CD001456

    Google Scholar 

  5. Rojas-Reyes MX, Morley CJ, Soll R: Prophylactic versus selective use of surfactant in preventing morbidity and mortality in preterm infants. Cochrane Database Syst Rev. 2012, 3: CD000510

    Google Scholar 

  6. Carbajal R, Eble B, Anand KJ: Premedication for tracheal intubation in neonates: confusion or controversy?. Semin Perinatol. 2007, 31: 309-317. 10.1053/j.semperi.2007.07.006.

    PubMed  Google Scholar 

  7. Durrmeyer X, Vutskits L, Anand KJ, Rimensberger PC: Use of analgesic and sedative drugs in the NICU: integrating clinical trials and laboratory data. Pediatr Res. 2010, 67: 117-127. 10.1203/PDR.0b013e3181c8eef3.

    PubMed  Google Scholar 

  8. Drasner K: Anesthetic effects on the developing nervous system: if you aren’t concerned, you haven’t been paying attention. Anesthesiology. 2010, 113: 10-12. 10.1097/ALN.0b013e3181dcd8b3.

    PubMed  Google Scholar 

  9. Dunn MS, Shennan AT, Zayack D, Possmayer F: Bovine surfactant replacement therapy in neonates of less than 30 weeks’ gestation: a randomized controlled trial of prophylaxis versus treatment. Pediatrics. 1991, 87: 377-386.

    CAS  PubMed  Google Scholar 

  10. Osborn DA, Jeffery HE, Bredemeyer SL, Polverino JM, Reid S: Targeted early rescue surfactant in ventilated preterm infants using the click test. Pediatrics. 2000, 106: E30-10.1542/peds.106.3.e30.

    CAS  PubMed  Google Scholar 

  11. Robert MF, Neff RK, Hubbell JP, Taeusch HW, Avery ME: Association between maternal diabetes and the respiratory-distress syndrome in the newborn. N Engl J Med. 1976, 294: 357-360. 10.1056/NEJM197602122940702.

    CAS  PubMed  Google Scholar 

  12. Delgado JC, Greene MF, Winkelman JW, Tanasijevic MJ: Comparison of disaturated phosphatidylcholine and fetal lung maturity surfactant/albumin ratio in diabetic and nondiabetic pregnancies. Am J Clin Pathol. 2000, 113: 233-239. 10.1309/7FMM-X2VR-HJKV-Q662.

    CAS  PubMed  Google Scholar 

  13. Tsai MY, Shultz EK, Williams PP, Bendel R, Butler J, Farb H, Wager G, Knox EG, Julian T, Thompson TR: Assay of disaturated phosphatidylcholine in amniotic fluid as a test of fetal lung maturity: experience with 2000 analyses. Clin Chem. 1987, 33: 1648-1651.

    CAS  PubMed  Google Scholar 

  14. Epaud R, Jonard L, Ducou-le-Pointe H, Delestrain C, Fanen P, Guillot L, Flamein F: Genetic disorders of surfactant. Arch Pediatr. 2012, 19: 212-219. 10.1016/j.arcped.2011.12.004.

    CAS  PubMed  Google Scholar 

  15. Gower WA, Nogee LM: Surfactant dysfunction. Paediatr Respir Rev. 2011, 12: 223-229. 10.1016/j.prrv.2011.01.005.

    PubMed  PubMed Central  Google Scholar 

  16. Nogee LM, de Mello DE, Dehner LP, Colten HR: Deficiency of pulmonary surfactant protein B in congenital alveolar proteinosis. N Engl J Med. 1993, 328: 406-410. 10.1056/NEJM199302113280606.

    CAS  PubMed  Google Scholar 

  17. Nogee LM, Dunbar AE, Wert SE, Askin F, Hamvas A, Whitsett JA: A mutation in the surfactant protein C gene associated with familial interstitial lung disease. N Engl J Med. 2001, 344: 573-579. 10.1056/NEJM200102223440805.

    CAS  PubMed  Google Scholar 

  18. Shulenin S, Nogee LM, Annilo T, Wert SE, Whitsett JA, Dean M: ABCA3 gene mutations in newborns with fatal surfactant deficiency. N Engl J Med. 2004, 350: 1296-1303. 10.1056/NEJMoa032178.

    CAS  PubMed  Google Scholar 

  19. Guillot L, Carré A, Szinnai G, Castanet M, Tron E, Jaubert F, Broutin I, Counil F, Feldmann D, Clement A, Polak M, Epaud R: NKX2-1 mutations leading to surfactant protein promoter dysregulation cause interstitial lung disease in “brain-lung-thyroid syndrome”. Hum Mutat. 2010, 31: E1146-E1162. 10.1002/humu.21183.

    PubMed  Google Scholar 

  20. Oh MH, Bae CW: Inhibitory effect of meconium on pulmonary surfactant function tested in vitro using the stable microbubble test. Eur J Pediatr. 2000, 159: 770-774. 10.1007/PL00008344.

    CAS  PubMed  Google Scholar 

  21. Bissinger R, Carlson C, Hulsey T, Eicher D: Secondary surfactant deficiency in neonates. J Perinatol. 2004, 24: 663-666. 10.1038/sj.jp.7211154.

    PubMed  Google Scholar 

  22. Angus DC, Linde-Zwirble WT, Clermont G, Griffin MF, Clark RH: Epidemiology of neonatal respiratory failure in the United States: projections from California and New York. Am J Respir Crit Care Med. 2001, 164: 1154-1160. 10.1164/ajrccm.164.7.2012126.

    CAS  PubMed  Google Scholar 

  23. Hibbard JU, Wilkins I, Sun L, Gregory K, Haberman S, Hoffman M, Kominiarek MA, Reddy U, Bailit J, Branch DW, Burkman R, Gonzalez Quintero VH, Hatjis CG, Landy H, Ramirez M, VanVeldhuisen P, Troendle J, Zhang J, Consortium on Safe Labor: Respiratory morbidity in late preterm births. JAMA. 2010, 304: 419-425.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Morrison JJ, Rennie JM, Milton PJ: Neonatal respiratory morbidity and mode of delivery at term: influence of timing of elective caesarean section. Br J Obstet Gynaecol. 1995, 102: 101-106. 10.1111/j.1471-0528.1995.tb09060.x.

    CAS  PubMed  Google Scholar 

  25. Zanardo V, Simbi AK, Franzoi M, Soldà G, Salvadori A, Trevisanuto D: Neonatal respiratory morbidity risk and mode of delivery at term: influence of timing of elective caesarean delivery. Acta Paediatr. 2004, 93: 643-647. 10.1111/j.1651-2227.2004.tb02990.x.

    CAS  PubMed  Google Scholar 

  26. Clark RH: The epidemiology of respiratory failure in neonates born at an estimated gestational age of 34 weeks or more. J Perinatol. 2005, 25: 251-257. 10.1038/sj.jp.7211242.

    PubMed  Google Scholar 

  27. Machado LU, Fiori HH, Baldisserotto M, Ramos Garcia PC, Vieira AC, Fiori RM: Surfactant deficiency in transient tachypnea of the newborn. J Pediatr. 2011, 159: 750-754. 10.1016/j.jpeds.2011.04.023.

    CAS  PubMed  Google Scholar 

  28. Holm BA, Notter RH: Effects of hemoglobin and cell membrane lipids on pulmonary surfactant activity. J Appl Physiol. 1987, 63: 1434-1442.

    CAS  PubMed  Google Scholar 

  29. Wang Z, Notter RH: Additivity of protein and nonprotein inhibitors of lung surfactant activity. Am J Respir Crit Care Med. 1998, 158: 28-35. 10.1164/ajrccm.158.1.9709041.

    CAS  PubMed  Google Scholar 

  30. Pandit PB, Dunn MS, Colucci EA: Surfactant therapy in neonates with respiratory deterioration due to pulmonary hemorrhage. Pediatrics. 1995, 95: 32-36.

    CAS  PubMed  Google Scholar 

  31. Amizuka T, Shimizu H, Niida Y, Ogawa Y: Surfactant therapy in neonates with respiratory failure due to haemorrhagic pulmonary oedema. Eur J Pediatr. 2003, 162: 697-702. 10.1007/s00431-003-1276-x.

    CAS  PubMed  Google Scholar 

  32. Neumayr TM, Watson AM, Wylam ME, Ouellette Y: Surfactant treatment of an infant with acute idiopathic pulmonary hemorrhage. Pediatr Crit Care Med. 2008, 9: e4-e6. 10.1097/01.PCC.0000298755.86878.20.

    PubMed  Google Scholar 

  33. Haas NA, Kulasekaran K, Camphausen CK: Successful use of surfactant to treat severe intrapulmonary hemorrhage after iatrogenic lung injury–a case report. Pediatr Crit Care Med. 2006, 7: 583-585. 10.1097/01.PCC.0000244405.96885.96.

    PubMed  Google Scholar 

  34. Aziz A, Ohlsson A: Surfactant for pulmonary haemorrhage in neonates. Cochrane Database Syst Rev. 2012, 7: CD005254

    Google Scholar 

  35. Dargaville PA, Copnell B, Mills JF, Haron I, Lee JK, Tingay DG, Rohana J, Mildenhall LF, Jeng MJ, Narayanan A, Battin MR, Kuschel CA, Sadowsky JL, Patel H, Kilburn CJ, Carlin JB, Morley CJ, lessMAS Trial Study Group: Randomized controlled trial of lung lavage with dilute surfactant for meconium aspiration syndrome. J Pediatr. 2011, 158: 383-389. 10.1016/j.jpeds.2010.08.044.

    CAS  PubMed  Google Scholar 

  36. Beligere N, Rao R: Neurodevelopmental outcome of infants with meconium aspiration syndrome: report of a study and literature review. J Perinatol. 2008, 28: S93-S101.

    PubMed  Google Scholar 

  37. Tyler DC, Murphy J, Cheney FW: Mechanical and chemical damage to lung tissue caused by meconium aspiration. Pediatrics. 1978, 62: 454-459.

    CAS  PubMed  Google Scholar 

  38. Tran N, Lowe C, Sivieri EM, Shaffer TH: Sequential effects of acute meconium obstruction on pulmonary function. Pediatr Res. 1980, 14: 34-38. 10.1203/00006450-198001000-00009.

    CAS  PubMed  Google Scholar 

  39. Cleary GM, Antunes MJ, Ciesielka DA, Higgins ST, Spitzer AR, Chander A: Exudative lung injury is associated with decreased levels of surfactant proteins in a rat model of meconium aspiration. Pediatrics. 1997, 100: 998-1003. 10.1542/peds.100.6.998.

    CAS  PubMed  Google Scholar 

  40. Moses D, Holm BA, Spitale P, Liu MY, Enhorning G: Inhibition of pulmonary surfactant function by meconium. Am J Obstet Gynecol. 1991, 164: 477-481. 10.1016/S0002-9378(11)80003-7.

    CAS  PubMed  Google Scholar 

  41. Bae CW, Takahashi A, Chida S, Sasaki M: Morphology and function of pulmonary surfactant inhibited by meconium. Pediatr Res. 1998, 44: 187-191. 10.1203/00006450-199808000-00008.

    CAS  PubMed  Google Scholar 

  42. Wiswell TE, Bley JA, Turner BS, Hunt RE, Fritz DL: Different high-frequency ventilator strategies: effect on the propagation of tracheobronchial histopathologic changes. Pediatrics. 1990, 85: 70-78.

    CAS  PubMed  Google Scholar 

  43. Dargaville PA, Copnell B, Australian and New Zealand Neonatal Network: The epidemiology of meconium aspiration syndrome: incidence, risk factors, therapies, and outcome. Pediatrics. 2006, 117: 1712-1721. 10.1542/peds.2005-2215.

    PubMed  Google Scholar 

  44. El Shahed AI, Dargaville P, Ohlsson A, Soll RF: Surfactant for meconium aspiration syndrome in full term/near term infants. Cochrane Database Syst Rev. 2007, 3: CD002054

    Google Scholar 

  45. Dargaville PA, Mills JF, Headley BM, Chan Y, Coleman L, Loughnan PM, Morley CJ: Therapeutic lung lavage in the piglet model of meconium aspiration syndrome. Am J Respir Crit Care Med. 2003, 168: 456-463. 10.1164/rccm.200301-121OC.

    PubMed  Google Scholar 

  46. Lista G, Bianchi S, Castoldi F, Fontana P, Cavigioli F: Bronchoalveolar lavage with diluted porcine surfactant in mechanically ventilated term infants with meconium aspiration syndrome. Clin Drug Investig. 2006, 26: 13-19. 10.2165/00044011-200626010-00002.

    CAS  PubMed  Google Scholar 

  47. Dargaville PA, Mills JF, Copnell B, Loughnan PM, McDougall PN, Morley CJ: Therapeutic lung lavage in meconium aspiration syndrome: a preliminary report. J Paediatr Child Health. 2007, 43: 539-545. 10.1111/j.1440-1754.2007.01130.x.

    PubMed  Google Scholar 

  48. Hahn S, Choi HJ, Soll R, Dargaville PA: Lung lavage for meconium aspiration syndrome in newborn infants. Cochrane Database Syst Rev. 2013, 4: CD003486

    Google Scholar 

  49. Rey-Santano C, Alvarez-Diaz FJ, Mielgo V, Murgia X, Lafuente H, Ruiz-Del-Yerro E, Valls-I-Soler A, Gastiasoro E: Bronchoalveolar lavage versus bolus administration of lucinactant, a synthetic surfactant in meconium aspiration in newborn lambs. Pediatr Pulmonol. 2011, 46: 991-999. 10.1002/ppul.21460.

    CAS  PubMed  Google Scholar 

  50. Benachi A, Chailley-Heu B, Barlier-Mur AM, Dumez Y, Bourbon J: Expression of surfactant proteins and thyroid transcription factor 1 in an ovine model of congenital diaphragmatic hernia. J Pediatr Surg. 2002, 37: 1393-1398. 10.1053/jpsu.2002.35375.

    PubMed  Google Scholar 

  51. Thébaud B, Barlier-Mur AM, Chailley-Heu B, Henrion-Caude A, Tibboel D, Dinh-Xuan AT, Bourbon JR: Restoring effects of vitamin A on surfactant synthesis in nitrofen-induced congenital diaphragmatic hernia in rats. Am J Respir Crit Care Med. 2001, 164: 1083-1089. 10.1164/ajrccm.164.6.2010115.

    PubMed  Google Scholar 

  52. Kinsella JP, Greenough A, Abman SH: Bronchopulmonary dysplasia. Lancet. 2006, 367: 1421-1431. 10.1016/S0140-6736(06)68615-7.

    PubMed  Google Scholar 

  53. Lally KP, Lally PA, Langham MR, Hirschl R, Moya FR, Tibboel D, Van Meurs K, Congenital Diaphragmatic Hernia Study Group: Surfactant does not improve survival rate in preterm infants with congenital diaphragmatic hernia. J Pediatr Surg. 2004, 39: 829-833.

    PubMed  Google Scholar 

  54. Van Meurs K, Congenital Diaphragmatic Hernia Study Group: Is surfactant therapy beneficial in the treatment of the term newborn infant with congenital diaphragmatic hernia?. J Pediatr. 2004, 145: 312-316. 10.1016/j.jpeds.2004.04.056.

    CAS  PubMed  Google Scholar 

  55. Moya FR, Thomas VL, Romaguera J, Mysore MR, Maberry M, Bernard A, Freund M: Fetal lung maturation in congenital diaphragmatic hernia. Am J Obstet Gynecol. 1995, 173: 1401-1405. 10.1016/0002-9378(95)90624-X.

    CAS  PubMed  Google Scholar 

  56. Mysore MR, Margraf LR, Jaramillo MA, Breed DR, Chau VL, Arévalo M, Moya FR: Surfactant protein A is decreased in a rat model of congenital diaphragmatic hernia. Am J Respir Crit Care Med. 1998, 157: 654-657. 10.1164/ajrccm.157.2.9612072.

    CAS  PubMed  Google Scholar 

  57. Boucherat O, Benachi A, Chailley-Heu B, Franco-Montoya ML, Elie C, Martinovic J, Bourbon JR: Surfactant maturation is not delayed in human fetuses with diaphragmatic hernia. PLoS Med. 2007, 4: e237-10.1371/journal.pmed.0040237.

    PubMed  PubMed Central  Google Scholar 

  58. Janssen DJ, Zimmermann LJ, Cogo P, Hamvas A, Bohlin K, Luijendijk IH, Wattimena D, Carnielli VP, Tibboel D: Decreased surfactant phosphatidylcholine synthesis in neonates with congenital diaphragmatic hernia during extracorporeal membrane oxygenation. Intensive Care Med. 2009, 35: 1754-1760. 10.1007/s00134-009-1564-7.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Awasthi S, Coalson JJ, Crouch E, Yang F, King RJ: Surfactant proteins A and D in premature baboons with chronic lung injury (Bronchopulmonary dysplasia): evidence for an inhibition of secretion. Am J Respir Crit Care Med. 1999, 160: 942-949. 10.1164/ajrccm.160.3.9806061.

    CAS  PubMed  Google Scholar 

  60. Merrill JD, Ballard RA, Cnaan A, Hibbs AM, Godinez RI, Godinez MH, Truog WE, Ballard PL: Dysfunction of pulmonary surfactant in chronically ventilated premature infants. Pediatr Res. 2004, 56: 918-926. 10.1203/01.PDR.0000145565.45490.D9.

    CAS  PubMed  Google Scholar 

  61. Pandit PB, Dunn MS, Kelly EN, Perlman M: Surfactant replacement in neonates with early chronic lung disease. Pediatrics. 1995, 95: 851-854.

    CAS  PubMed  Google Scholar 

  62. Laughon M, Bose C, Moya F, Aschner J, Donn SM, Morabito C, Cummings JJ, Segal R, Guardia C, Liu G, Surfaxin Study Group: A pilot randomized, controlled trial of later treatment with a peptide-containing, synthetic surfactant for the prevention of bronchopulmonary dysplasia. Pediatrics. 2009, 123: 89-96. 10.1542/peds.2007-2680.

    PubMed  Google Scholar 

  63. Sweet DG, Halliday HL: The use of surfactants in 2009. Arch Dis Child Educ Pract Ed. 2009, 94: 78-83. 10.1136/adc.2008.153023.

    CAS  PubMed  Google Scholar 

  64. Plavka R, Kopecký P, Sebron V, Leiská A, Svihovec P, Ruffer J, Dokoupilová M, Zlatohlávková B, Janus V, Keszler M: Early versus delayed surfactant administration in extremely premature neonates with respiratory distress syndrome ventilated by high-frequency oscillatory ventilation. Intensive Care Med. 2002, 28: 1483-1490. 10.1007/s00134-002-1440-1.

    PubMed  Google Scholar 

  65. The OSIRIS Collaborative Group: Early versus delayed neonatal administration of a synthetic surfactant - the judgement of OSIRIS: the OSIRIS collaborative group (open study of infants at high risk of or with respiratory insufficiency - the role of surfactant. Lancet. 1992, 340: 1363-1369. 10.1016/0140-6736(92)92557-V.

    Google Scholar 

  66. Lefort S, Diniz EM, Vaz FA: Clinical course of premature infants intubated in the delivery room, submitted or not to porcine-derived lung surfactant therapy within the first hour of life. J Matern Fetal Neonatal Med. 2003, 14: 187-196. 10.1080/jmf.14.3.187.196.

    CAS  PubMed  Google Scholar 

  67. Konishi M, Fujiwara T, Chida S, Maeta H, Shimada S, Kasai T, Fujii Y, Murakami Y: A prospective randomized trial of early versus late administration of a single dose of surfactant-TA. Early Hum Dev. 1992, 29: 275-282. 10.1016/0378-3782(92)90164-C.

    CAS  PubMed  Google Scholar 

  68. Gortner L, Wauer RR, Hammer H, Stock GJ, Heitmann F, Reiter HL, Kühl PG, Möller JC, Friedrich HJ, Reiss I, Hentschel R, Jorch G, Hieronimi G, Kuhls E: Early versus late surfactant treatment in preterm infants of 27 to 32 weeks’ gestational age: a multicenter controlled clinical trial. Pediatrics. 1998, 102: 1153-1160. 10.1542/peds.102.5.1153.

    CAS  PubMed  Google Scholar 

  69. European Exosurf Study Group: Early or selective surfactant (Colfosceril Palmitate, Exosurf) for intubated babies at 26 to 29 weeks gestation: a European double-blind trial with sequential analysis. Online J Curr Clin Trials. 1992, Doc No 28:[3886 words; 47 paragraphs]

    Google Scholar 

  70. Kandraju H, Murki S, Subramanian S, Gaddam P, Deorari A, Kumar P: Early routine versus late selective surfactant in preterm neonates with respiratory distress syndrome on nasal continuous positive airway pressure: a randomized controlled trial. Neonatology. 2013, 103: 148-154. 10.1159/000345198.

    PubMed  Google Scholar 

  71. Dilmen U, Ozdemir R, Aksoy HT, Uras N, Demirel N, Kırimi E, Erdeve O, Ozer E, Baş AY, Gürsoy T, Zenciroğlu A, Ovalı F, Oğuz SS: Early regular versus late selective poractant treatment in preterm infants born between 25 and 30 gestational weeks: a prospective randomized multicentre study. J Matern Fetal Neonatal Med. 2013, in press

    Google Scholar 

  72. British Association of Perinatal Medecine RDS/Surfactant Guidelines Group: Guidelines for good practice in the management of respiratory distress syndrome. 1999, http://www.bapm.org,

    Google Scholar 

  73. Engle WA, American Academy of Pediatrics Committee on Fetus and Newborn: Surfactant-replacement therapy for respiratory distress in the preterm and term neonate. Pediatrics. 2008, 121: 419-432. 10.1542/peds.2007-3283.

    PubMed  Google Scholar 

  74. Fetus and Newborn Committee, Canadian Paediatric Society: Recommendations for neonatal surfactant therapy. Paediatr Child Health. 2005, 10: 109-116.

    Google Scholar 

  75. Sweet DG, Carnielli V, Greisen G, Hallman M, Ozek E, Plavka R, Saugstad OD, Simeoni U, Speer CP, Halliday HL, European Association of Perinatal Medicine: European consensus guidelines on the management of neonatal respiratory distress syndrome in preterm infants - 2010 update. Neonatology. 2010, 97: 402-417. 10.1159/000297773.

    PubMed  Google Scholar 

  76. Sweet DG, Carnielli V, Greisen G, Hallman M, Ozek E, Plavka R, Saugstad OD, Simeoni U, Speer CP, Vento M, Halliday HL: European consensus guidelines on the management of neonatal respiratory distress syndrome in preterminfants - 2013 update. Neonatology. 2013, 103: 353-368. 10.1159/000349928.

    PubMed  Google Scholar 

  77. Van Kaam AH, De Jaegere AP, Borensztajn D, Rimensberger PC, Neovent Study Group: Surfactant replacement therapy in preterm infants: a European survey. Neonatology. 2011, 100: 71-77. 10.1159/000322004.

    CAS  PubMed  Google Scholar 

  78. Morley CJ, Davis PG, Doyle LW, Brion LP, Hascoet JM, Carlin JB, COIN Trial Investigators: Nasal CPAP or intubation at birth for very preterm infants. N Engl J Med. 2008, 358: 700-708. 10.1056/NEJMoa072788.

    CAS  PubMed  Google Scholar 

  79. Rojas MA, Lozano JM, Rojas MX, Laughon M, Bose CL, Rondon MA, Charry L, Bastidas JA, Perez LA, Rojas C, Ovalle O, Celis LA, Garcia-Harker J, Jaramillo ML, Colombian Neonatal Research Network: Very early surfactant without mandatory ventilation in premature infants treated with early continuous positive airway pressure: a randomized, controlled trial. Pediatrics. 2009, 123: 137-142. 10.1542/peds.2007-3501.

    PubMed  Google Scholar 

  80. Sandri F, Plavka R, Ancora G, Simeoni U, Stranak Z, Martinelli S, Mosca F, Nona J, Thomson M, Verder H, Fabbri L, Halliday H, CURPAP Study Group: Prophylactic or early selective surfactant combined with nCPAP in very preterm infants. Pediatrics. 2010, 125: e1402-1409. 10.1542/peds.2009-2131.

    PubMed  Google Scholar 

  81. Finer NN, Carlo WA, Walsh MC, Rich W, Gantz MG, Laptook AR, Yoder BA, Faix RG, SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network, et al: Early CPAP versus surfactant in extremely preterm infants. N Engl J Med. 2010, 362: 1970-1979.

    CAS  PubMed  Google Scholar 

  82. Dunn MS, Kaempf J, de Klerk A, de Klerk R, Reilly M, Howard D, Ferrelli K, O’Conor J, Soll RF, Vermont Oxford Network DRM Study Group: Randomized trial comparing 3 approaches to the initial respiratory management of preterm neonates. Pediatrics. 2011, 128: e1069-1076. 10.1542/peds.2010-3848.

    PubMed  Google Scholar 

  83. Vaucher YE, Peralta-Carcelen M, Finer NN, Carlo WA, Gantz MG, Walsh MC, Laptook AR, Yoder BA, SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network, et al: Neurodevelopmental outcomes in the early CPAP and pulse oximetry trial. N Engl J Med. 2012, 367: 2495-2504. 10.1056/NEJMoa1208506.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Bhandari V, Gavino RG, Nedrelow JH, Pallela P, Salvador A, Ehrenkranz RA, Brodsky NL: A randomized controlled trial of synchronized nasal intermittent positive pressure ventilation in RDS. J Perinatol. 2007, 27: 697-703. 10.1038/sj.jp.7211805.

    CAS  PubMed  Google Scholar 

  85. Stevens TP, Harrington EW, Blennow M, Soll RF: Early surfactant administration with brief ventilation vs. selective surfactant and continued mechanical ventilation for preterm infants with or at risk for respiratory distress syndrome. Cochrane Database Syst Rev. 2007, 4: CD003063

    Google Scholar 

  86. Dani C, Corsini I, Bertini G, Pratesi S, Barp J, Rubaltelli FF: Effect of multiple INSURE procedures in extremely preterm infants. J Matern Fetal Neonatal Med. 2011, 24: 1427-1431. 10.3109/14767058.2011.572203.

    PubMed  Google Scholar 

  87. Kirsten GF, Kirsten CL, Henning PA, Smith J, Holgate SL, Bekker A, Kali GT, Harvey J: The outcome of ELBW infants treated with NCPAP and InSurE in a resource-limited institution. Pediatrics. 2012, 129: e952-959. 10.1542/peds.2011-1365.

    PubMed  Google Scholar 

  88. Kribs A: How best to administer surfactant to VLBW infants?. Arch Dis Child Fetal Neonatal Ed. 2011, 96: F238-240. 10.1136/adc.2010.209098.

    PubMed  Google Scholar 

  89. Kattwinkel J, Robinson M, Bloom BT, Delmore P, Ferguson JE: Technique for intrapartum administration of surfactant without requirement for an endotracheal tube. J Perinatol. 2004, 24: 360-365. 10.1038/sj.jp.7211103.

    CAS  PubMed  Google Scholar 

  90. Abdel-Latif ME, Osborn DA: Pharyngeal instillation of surfactant before the first breath for prevention of morbidity and mortality in preterm infants at risk of respiratory distress syndrome. Cochrane Database Syst Rev. 2011, 3: CD008311

    Google Scholar 

  91. Trevisanuto D, Grazzina N, Ferrarese P, Micaglio M, Verghese C, Zanardo V: Laryngeal mask airway used as a delivery conduit for the administration of surfactant to preterm infants with respiratory distress syndrome. Biol Neonate. 2005, 87: 217-220. 10.1159/000083370.

    CAS  PubMed  Google Scholar 

  92. Verder H, Agertoft L, Albertsen P, Christensen NC, Curstedt T, Ebbesen F, Greisen G, Hobolth N, Holm V, Jacobsen T, et al: Surfactant treatment of newborn infants with respiratory distress syndrome primarily treated with nasal continuous positive air pressure: a pilot study. Ugeskr Laeger. 1992, 154: 2136-2139.

    CAS  PubMed  Google Scholar 

  93. Göpel W, Kribs A, Ziegler A, Laux R, Hoehn T, Wieg C, Siegel J, Avenarius S, von der Wense A, Vochem M, Groneck P, Weller U, Möller J, Härtel C, Haller S, Roth B, Herting E, German Neonatal Network: Avoidance of mechanical ventilation by surfactant treatment of spontaneously breathing preterm infants (AMV): an open-label, randomised, controlled trial. Lancet. 2011, 378: 1627-1634. 10.1016/S0140-6736(11)60986-0.

    PubMed  Google Scholar 

  94. Dargaville PA, Aiyappan A, Cornelius A, Williams C, De Paoli AG: Preliminary evaluation of a new technique of minimally invasive surfactant therapy. Arch Dis Child Fetal Neonatal Ed. 2011, 96: F243-248. 10.1136/adc.2010.192518.

    PubMed  Google Scholar 

  95. Robillard E, Alarie Y, Dagenais-Perusse P, Baril E, Guilbeault A: Microaerosol administration of synthetic beta-gamma-dipalmitoyl-l-alpha-lecithin in the respiratory distress syndome: a preliminary report. Can Med Assoc J. 1964, 90: 55-57.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Chu J, Clements JA, Cotton EK, Klaus MH, Sweet AY, Tooley WH, Bradley BL, Brandorff LC: Neonatal pulmonary ischemia: I. clinical and physiological studies. Pediatrics. 1967, 40: 709-782.

    PubMed  Google Scholar 

  97. Mazela J, Merritt TA, Finer NN: Aerosolized surfactants. Curr Opin Pediatr. 2007, 19: 155-162. 10.1097/MOP.0b013e32807fb013.

    PubMed  Google Scholar 

  98. Lewis J, Ikegami M, Higuchi R, Jobe A, Absolom D: Nebulized vs. instilled exogenous surfactant in an adult lung injury model. J Appl Physiol. 1991, 71: 1270-1276.

    CAS  PubMed  Google Scholar 

  99. Bahlmann H, Sun B, Nilsson G, Curstedt T, Robertson B: Aerosolized surfactant in lung-lavaged adult rats: factors influencing the therapeutic response. Acta Anaesthesiol Scand. 2000, 44: 612-622. 10.1034/j.1399-6576.2000.00521.x.

    CAS  PubMed  Google Scholar 

  100. Lewis JF, Goffin J, Yue P, McCaig LA, Bjarneson D, Veldhuizen RA: Evaluation of exogenous surfactant treatment strategies in an adult model of acute lung injury. J Appl Physiol. 1996, 80: 1156-1164. 10.1063/1.362853.

    CAS  PubMed  Google Scholar 

  101. Ruppert C, Kuchenbuch T, Boensch M, Schmidt S, Mathes U, Hillebrand V, Henneke I, Markart P, Reiss I, Schermuly RT, Seeger W, Günther A: Dry powder aerosolization of a recombinant surfactant protein-C-based surfactant for inhalative treatment of the acutely inflamed lung. Crit Care Med. 2010, 38: 1584-1591. 10.1097/CCM.0b013e3181dfcb3b.

    CAS  PubMed  Google Scholar 

  102. Finer NN, Merritt TA, Bernstein G, Job L, Mazela J, Segal R: An open label, pilot study of Aerosurf® combined with nCPAP to prevent RDS in preterm neonates. J Aerosol Med Pulm Drug Deliv. 2010, 23: 303-309. 10.1089/jamp.2009.0758.

    CAS  PubMed  Google Scholar 

  103. Shah S: Exogenous surfactant: intubated present, nebulized future?. World J Pediatr. 2011, 7: 11-15. 10.1007/s12519-010-0201-4.

    PubMed  Google Scholar 

  104. Hentschel R, Jorch G: Acute side effects of surfactant treatment. J Perinat Med. 2002, 30: 143-148.

    PubMed  Google Scholar 

  105. Raju TN, Langenberg P: Pulmonary hemorrhage and exogenous surfactant therapy: a metaanalysis. J Pediatr. 1993, 123: 603-610. 10.1016/S0022-3476(05)80963-1.

    CAS  PubMed  Google Scholar 

  106. Bambang Oetomo S, Bos AF, de Lei L, Okken A, van Sonderen L, Halliday HL, Walti H: Immune response after surfactant treatment of newborn infants with respiratory distress syndrome. Biol Neonate. 1993, 64: 341-345. 10.1159/000244009.

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank all the members of the “French Young Neonatologist Club” for their fruitful discussions and critical reading of the review.

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    Authors and Affiliations

    1. Service de Médecine Néonatale de Port-Royal Groupe Hospitalier Cochin-Broca-Hôtel Dieu, APHP, Paris, France

      Emmanuel Lopez

    2. Réanimation et Médecine Néonatales, CHU d’Angers, Angers, France

      Géraldine Gascoin

    3. Département de pédecine néonatale, CHU de Nantes, Nantes, France

      Cyril Flamant

    4. Réanimation Néonatale, CH Sud Francilien, Corbeil-Essonnes, France

      Mona Merhi

    5. Médecine Néonatale, CHU d’Amiens, Amiens, France

      Pierre Tourneux

    6. Réanimation et Pédiatrie Néonatales, Groupe Hospitalier Robert Debré, APHP, 48 Bd Sérurier, Paris, 75019, France

      Olivier Baud

    Authors
    1. Emmanuel Lopez
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    2. Géraldine Gascoin
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    3. Cyril Flamant
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    4. Mona Merhi
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    5. Pierre Tourneux
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    6. Olivier Baud
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    for the French Young Neonatologist Club

    Corresponding author

    Correspondence to Olivier Baud.

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    Competing interests

    The authors declare that they have no competing interests.

    Authors’ contributions

    EL wrote the “WHEN SHOULD PRETERM INFANTS WITH RDS BE TREATED WITH EXOGENOUS SURFACTANT?” section. PT wrote the “WHICH INFANTS SHOULD WE TREAT WITH EXOGENOUS SURFACTANT THERAPY?” section. GG, CF and MM wrote the “HOW SHOULD PRETERM INFANTS WITH RDS BE TREATED WITH EXOGENOUS SURFACTANT: INSURE OR MIST?” section. OB conceived of the organization of the review, participated in its coordination and helped to draft the manuscript. All authors from the “French Young Neonatologist Club” read and approved the final manuscript.

    Emmanuel Lopez, Géraldine Gascoin contributed equally to this work.

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    Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/2.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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    Lopez, E., Gascoin, G., Flamant, C. et al. Exogenous surfactant therapy in 2013: what is next? who, when and how should we treat newborn infants in the future?. BMC Pediatr 13, 165 (2013). https://doi.org/10.1186/1471-2431-13-165

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    • DOI: https://doi.org/10.1186/1471-2431-13-165

    Keywords

    BMC Pediatrics

    ISSN: 1471-2431

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