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Immediate respiratory management of the preterm infant
Seminars in Fetal & Neonatal Medicine (2008) 13, 24e29
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/siny
Immediate respiratory management of the preterm infant Sunil K. Sinha a,b,*, Samir Gupta b, Steven M. Donn c a
Paediatrics and Neonatal Medicine, University of Durham, Durham, UK The James Cook University Hospital, Middlesbrough TS4 3BW, UK c Department of Pediatrics, Division of Neonatal-Perinatal Medicine, University of Michigan Health System, C.S. Mott Children’s Hospital, Ann Arbor, MI 48103, USA b
KEYWORDS Chronic lung disease; Continuous positive airway pressure (CPAP); Prematurity; Respiratory distress syndrome (RDS); Surfactant
Summary Infants born prematurely have underdeveloped lungs characterised by both morphological and biochemical abnormalities. Respiratory distress syndrome (RDS) is the leading cause of morbidity and mortality in this population. Both surfactant replacement therapy with mechanical ventilation and continuous positive airway pressure (CPAP) have been shown to be of benefit. However, considerable controversy exists about how best to use these therapies. This paper will review the pathophysiology of RDS and the evidence supporting each of these treatments. ª 2007 Elsevier Ltd. All rights reserved.
Introduction Respiratory distress syndrome (RDS) is a disorder of the preterm lung and is a leading cause of death and pulmonary morbidity in babies born prematurely. The incidence and severity of RDS is inversely proportional to gestational age. RDS has both unique biochemical and morphological characteristics. Abnormalities in pulmonary histology and cytoarchitecture include insufficient alveolarisation, diminished functional surface area, an increased distance from the alveolus to its adjacent capillary, deposition of fibrin into the air spaces, and pulmonary arteriolar muscularinisation. The biochemical abnormality is the deficiency of surfactant, which leads to increased alveolar surface tension and collapse, progressive atelectasis and decreased * Corresponding author. Paediatrics and Neonatal Medicine, University of Durham, Durham, UK. E-mail address: [email protected] (S.K. Sinha).
pulmonary compliance. Affected infants frequently require mechanical ventilation and are at risk for ventilatorinduced lung injury, and 30e40% develop chronic lung disease (CLD), sometimes severe enough to interfere with normal growth and development.1 Respiratory maladaptation at birth can also result from a number of other causes, including an abnormal transition of the fetus from the intrauterine to extrauterine environment. The hallmark of normal transition is the conversion of the fluid-filled lungs into a hollow organ distended with air and capable of gaseous exchange sufficient to support life. The majority of babies born beyond 32 weeks of gestation will establish normal respiration without much help after delivery. However, the situation is different for infants born at an earlier gestational age because of the propensity to develop RDS. Any supportive care provided in the immediate neonatal period must be based on an understanding of the pathophysiology of these homeostatic mechanisms.
1744-165X/$ - see front matter ª 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.siny.2007.09.006
Respiratory management of preterm infant Human lung development goes through various stages including pseudoglandular (5e17 weeks), canalicular (16e 26 weeks), saccular (24e38 weeks) and finally alveolar (36 weeks to 2 years). During intrauterine development, the fetal lungs are filled with liquid secreted by the pulmonary epithelium. The volume and rate at which the liquid is secreted into the fetal lungs are calibrated to maintain lung volume at about functional residual capacity (FRC) and are the major determinants of normal lung growth. After birth, the pulmonary fluid is actively absorbed, and with introduction of air into the lungs, an air/liquid interface, facilitated by surfactant, forms the alveolar lining. The physical properties of the surfactant lining are such that the surface tension effect at the air/liquid interface is minimised, facilitating alveolar expansion and preventing the collapse of small alveoli, in accordance with LaPlace principle.2 Another important event is the transition from fetal respiratory activity to normal ventilation (establishing spontaneous breathing) soon after birth. During spontaneous breathing, the driving pressure required to overcome elastic, air-flow-resistive and inertial properties of the respiratory system is the result of intrapleural pressure (PIP) changes generated by the respiratory muscles. Factors that influence the respiratory muscles and respiratory mechanics have an effect on how air flows into and out of the lungs. The process of spontaneous breathing generally occurs at about one-third of total lung capacity, so that two-thirds of the total capacity is available as reserve. The capacity of the lungs can be represented in four different ways: total lung capacity, vital capacity, inspiratory capacity and functional residual capacity (FRC). FRC is the volume of gas in the lungs at the end of a normal expiration and is in continuity with the airways. A normal FRC enables optimal lung mechanics and alveolar surface area for efficient ventilation and gas exchange. The physiological processes that facilitate the onset of postnatal pulmonary gas exchange include: 1. The effect of ventilation on reducing pulmonary vascular resistance. 2. The effect of a more alkaline pH on reducing pulmonary vascular resistance to facilitate pulmonary blood flow. 3. Successful establishment of respiration to achieve an optimal FRC. 4. The effect of driving pressure to maintain optimal tidal volume. The majority of babies born at higher gestational ages will establish normal respiratory and circulatory function without help. However, a significant proportion of those who are born too early may experience difficulties in dealing with these normal adaptive processes and may die as a consequence, unless appropriately supported. Supportive treatments include exogenous surfactant replacement therapy (with attendant intubation and at least a brief period of positive pressure ventilation) and/or continuous positive airway pressure (CPAP). Some babies, particularly those born before 28 weeks of gestation, will still require assisted ventilation.
25
Current therapeutic options: how do they work? Pulmonary surfactant is a multicomponent compound of several phospholipids, neutral lipids and associated proteins. Of the phospholipids, dipalmitoyl phosphatidylcholine is the most prevalent component, with a structure that is well suited to form a stable monolayer required to generate the low surface tension to prevent alveolar collapse at end-expiration. Administration of exogenous surfactant to a surfactant-deficient preterm newborn decreases the minimum pressure required to open the lungs, increases the maximal lung volume, and prevents lung collapse at low pressure. These effects produce a hysteresis in surface tension versus surface area, allowing uniform expansion and contraction of normal alveoli. Instilling surfactant before the onset of RDS has been shown to partially avoid barotrauma and ventilator-induced lung injury resulting from mechanical ventilation.3 CPAP is positive pressure applied to the airways of a spontaneously breathing baby throughout the respiratory cycle. The rationale for use of CPAP is to support the airways and avoid alveolar collapse to a level below FRC. The premature baby has an immature lung structure with relatively undeveloped internal architecture to maintain lung volume, so that it is not held open by internal support. Moreover, the chest wall of the premature baby is soft and pliable, and thus not capable of holding the lung open during excessive inspiratory effort. Additionally, the pull of the diaphragm (and thus the negative pressure generated) distorts the chest wall and reduces the tidal volume. CPAP reduces the likelihood of upper airway collapse and decreases upper airway resistance by mechanically splinting it open. It increases the pharyngeal cross-sectional area and decreases genioglossus activity. CPAP also alters the shape of the diaphragm and increases its activity, improves lung compliance, and decreases airway resistance. This allows a greater tidal volume for a given negative pressure, with subsequent reduction in the work of breathing. CPAP also seems to conserve surfactant on the alveolar surface, and therefore may have a synergistic effect.4
Evidence of effectiveness Exogenous surfactant replacement therapy Surfactant therapy, whether used as treatment or prophylaxis, is well known to reduce morbidity and mortality in newborns with or at risk for RDS. Timing of surfactant administration, and to some extent, type of surfactant used, are important considerations. A meta-analysis compared the effect of early (less than 2 h) versus delayed rescue administration of surfactant therapy in infants intubated for RDS. The results demonstrated that early treatment significantly reduces the incidence of pneumothorax, pulmonary interstitial emphysema, CLD, and mortality compared to delayed treatment. This meta-analysis included one prevention trial (Exosurf versus Infasurf) and 10 treatment trials (seven trials comparing Exosurf with Survanta; one trial comparing Exosurf with Infasurf;
26 one trial comparing ALEC with Curosurf; and one trial comparing Curosurf with Exosurf). This review concluded that all types of surfactants are effective in the treatment and prevention of RDS, but suggested that use of animalderived surfactant resulted in fewer deaths (number needed to treat [NNT Z 37]), greater reduction in the level of ventilatory support, and a lower incidence of pneumothorax (NNT Z 20) compared to synthetic products, which do not contain the associated proteins.5 The beneficial effects of animal-derived surfactants were thought to be related to the protein content of these preparations. No reduction in the incidence of bronchopulmonary dysplasia (BPD) was reported in this review or in any of the individual trials included. Interpretation of the findings of this meta-analysis, however, should be viewed with caution, as the studies included were quite heterogeneous in population characteristics, entry criteria and primary outcomes. Many of these trials were not blinded, while the surfactants used in these trials also differed in their key components, volume of administration and dose of phospholipids. It is quite possible that the advantages attributed to the animal-derived surfactants in this metaanalysis might have been inadvertently exaggerated.6,7 More recently, newer synthetic surfactants have been developed. One of these is Surfaxin, a synthetic surfactant containing an artificial peptide (Sinapultide), which mimics the biological properties of human surfactant protein B. Surfaxin was found to be as good as, if not superior to, currently available animal-derived surfactants.8
CPAP and resuscitation The data from animal studies suggest that providing positive end-expiratory pressure (PEEP) during resuscitation reduces the alveolar-arterial oxygen gradient proportional to the level of PEEP applied,9 lowers indicators of acute lung injury,10 improves alveolar surfactant pool size,11 and improves oxygenation12 and ventilation/perfusion matching.13 Both observational and cohort studies have examined CPAP use after initial resuscitation in the delivery room as a treatment for RDS. They have consistently shown that it is feasible to use CPAP in a select group of infants with reduction in the need for mechanical ventilation. The only randomised controlled trial (RCT) during resuscitation was a pilot trial reported by Finer et al., who randomised 104 infants <28 weeks of gestation to CPAP or no positive pressure after delivery. Only 4 of the 43 infants weighing <700 g and 3 of the 37 infants <25 weeks of gestation were able to be resuscitated successfully with CPAP alone; overall, 80% of study infants had to be intubated within the first 7 days of life. The result of this study confirms the impression that CPAP alone is unlikely to succeed in this cohort of very immature infants.14
CPAP and RDS Although there is no doubt that use of CPAP post-extubation is beneficial and helps to reduce extubation failure after positive pressure ventilation,15 it still remains a moot point whether early use of CPAP, starting at birth, has the same
S.K. Sinha et al. benefit in terms of patient outcomes. The stimulus to use CPAP at birth as a mode of support for very low birthweight infants comes from an observation by Avery et al.,16 subsequently confirmed by Van Marter et al.,17 who did a retrospective review of contemporary practices and clinical outcomes in a number of neonatal units in the USA. They observed a significantly lower incidence of CLD in a unit at Columbia University, which had a much greater use of CPAP compared to the others who used mainly intubation and mechanical ventilation as a primary treatment strategy. The unit also used markedly less surfactant (10% versus 45%), and yet was able to maintain a low rate of CLD compared to the other regional centres. Interestingly, this observation also found that the use of mechanical ventilation on day 1 increased the odds of developing CLD 13fold, with a decreasing odds ratio associated with initiation of mechanical ventilation later in the first week of life. These practices, however, preceded the ‘surfactant era’ at a time when the use of antenatal corticosteroids was also low. Coincident with development of exogenous surfactant therapy, interest in primary CPAP therapy waned. Since then, however, there has been a resurgence of interest in CPAP, so much so that it is now becoming a common practice in many neonatal units despite a lack of clear evidence of its efficacy and safety. We also do not know what group of babies is most likely to benefit from early CPAP treatment, what level of CPAP is safe, what device to use e fixed flow versus variable flow e and whether CPAP’s short-term benefit is maintained, as there are no longterm follow-up data available.18 The recent experience from Columbia University has been presented in more depth by Ammari et al.19 who reviewed the courses of 261 infants <1250 g and reported their outcomes at 72 h of age based on the initial respiratory support modality. The researchers divided the infants into two groups: (1) CPAP-started group; and (2) ventilatorstarted group. The CPAP group was further subdivided into ‘CPAP success’ or ‘CPAP failure’. They observed that infants who succeeded on CPAP were about 3 weeks more mature and weighed about 300 g more than those who failed CPAP therapy (p < 0.001). The ventilator-started infants were about 30 times more likely to have received positive pressure via bag and mask at delivery than infants who were started on CPAP (91% versus 24%; OR Z 29.9; 95% CI 8.8, 102). Death occurred in 21/32 (66%) ventilator-started infants compared to only 20/229 (9%) CPAP-started infants. Mortality in the CPAP failure group was 18/55 (33%), and mortality in the CPAP success group was 2/174 (1%). However, such data have to be interpreted with caution because the differences might be influenced by a variety of factors, including condition at birth and severity of lung disease. Notably, only 51% of the infants who were CPAP failures and 53% of infants ventilated from birth received surfactant. Withholding surfactant treatment in such cases might have contributed to both mortality and morbidity and cannot be evaluated because of incomplete patient details.
Combination therapy: surfactant and CPAP There are limited data on the combined use of CPAP and surfactant immediately after birth. Verder et al.20
Respiratory management of preterm infant reported an RCT of infants with moderate-to-severe surfactant deficiency treated with nasal CPAP and a single dose of Curosurf given during a brief period of intubation. This significantly reduced the need for subsequent mechanical ventilation during the first 7 days. The study was criticised because babies >30 weeks were included and treatment was given late (median age 12 h). In a subsequent RCT,21 these investigators confined enrolment to babies <30 weeks of gestation and reported that the combined use of early CPAP with earlier administration of Curosurf resulted in a significant reduction in the need for mechanical ventilation. In both of these trials, there were no differences in death or BPD when compared to the control group. Although it proved the superiority of combining surfactant with CPAP compared to CPAP alone, it did not answer the question of whether early CPAP and surfactant is better than mechanical ventilation following surfactant administration. In another multicentre RCT, Thomson22 randomised infants into four groups: (1) early CPAP with prophylactic surfactant; (2) early CPAP with rescue surfactant; (3) early mechanical ventilation (intermittent positive pressure ventilation [IPPV]) with prophylactic surfactant; and (4) conventional management, with rescue IPPV and rescue surfactant treatment, if needed. There was no difference in the total respiratory support (mechanical ventilation and CPAP) until discharge or CLD among the groups. This study confirmed the observation that CPAP, with or without prophylactic surfactant, reduces the need for mechanical ventilation when applied as the initial respiratory support. This study, however, excluded babies <27 weeks, who are the most vulnerable group. To date, there have been no prospective studies comparing the use of early CPAP versus prophylactic or early surfactant in the extremely premature and most vulnerable infants. Although individual units report their successes with early CPAP in very low birthweight infants, the use and timing of surfactant administration in such infants, either before the use of CPAP or for infants who failed CPAP, have not been consistently reported. This underscores the need for an RCT of early CPAP versus the most evidence-based intervention, prophylactic or early surfactant.
On the horizon So far, most of the information on the early use of CPAP has come from retrospective cohort studies, but results of RCTs have started to appear, which should provide a better level of evidence. One such study, recently published in abstract form is the COIN trial.23 This trial examined the feasibility of early CPAP in babies <29 weeks of gestation in a multicentre RCT, in which 610 preterm babies 25e28 weeks of gestation were randomised to receive either CPAP (8 cm H2O) or intubation and ventilation immediately after birth. A third of the enrolled babies were 25e26 weeks of gestation. At 28 days postnatal age, the CPAP group had fewer deaths or need for supplemental oxygen (OR Z 0.63; 95% CI 0.46, 0.86; p Z 0.006). This advantage was, however, lost at 36 weeks of PMA. The intubation rate in the first 5 days for the CPAP group was 46% (55%
27 for 25e26 weeks and 40% for 27e28 weeks). There were no significant difference in the duration of respiratory support or the incidence of complications related to prematurity, but there was a significant increase in the rate of pneumothorax in the CPAP group (9% versus 3%). Although this trial showed that babies aged 25e28 weeks, who breathe spontaneously at birth, can be successfully managed with early CPAP, the denominator of the total number of preterm infants between 25 and 28 weeks of gestation requiring respiratory support at birth during the study period was not provided and thus it is difficult to extrapolate the findings to the general population of extremely preterm babies. There are at least two further ongoing RCTs on nasal CPAP, which should provide some useful information when completed.24 The VermonteOxford Network is now enrolling infants in a 3-armed trial in which infants born at 26e29 weeks of gestation are being randomised after 6 days to one of three groups: (1) intubation, early prophylactic surfactant, and subsequent stabilisation on mechanical ventilation; (2) intubation, early prophylactic surfactant, and rapid extubation to CPAP; and (3) early stabilisation with nasal CPAP, with selective intubation and surfactant administration according to clinical guidelines. This trial is also not recruiting infants <26 weeks, which will leave the question about what to do with the most vulnerable group unanswered (http://www.vtoxford.org/home.aspx?pZ research/drm/index.htm). Another trial (SUPPORT) is currently enrolling infants of 24e27 weeks of gestation and randomising to either CPAP beginning in the delivery room with criteria for subsequent intubation, or intubation with surfactant treatment within 1 h of birth with continuing mechanical ventilation.
Aerosolised surfactant The usefulness of exogenous surfactant therapy, either given prophylactically or as a rescue therapy, for both prevention and treatment of RDS, is well established. However, the administration of surfactant requires endotracheal intubation, which is not a benign procedure. If surfactant could be delivered by CPAP, as an aerosol, an effective compromise might be reached. Clinical studies for the treatment and prophylaxis of newborns with RDS have suggested the safety of this approach, but the results of these studies have been contradictory. In order to be successful, the surfactant would have to survive the aerosolisation process, be able to be delivered to the distal portions of the lung, reaggregate, and maintain biological activity. The method of delivery is also important as, hypothetically, the most efficient aerosolised surfactant system should use an aerosol flow equal or close to peak inspiratory flow (PIF) or a volume of aerosol equal to minute ventilation to avoid dilution.25 A recent clinical study with aerosolised lucinactant (Aerosurf) has shown the feasibility and safety of delivering this synthetic peptide-containing surfactant to newborns with early signs of RDS. In this pilot study, a vibrating membrane nebuliser (Aeroneb Pro, Artemis
28
S.K. Sinha et al.
Med, UK) was used to aerosolise 20 mg/mL Aerosurf. Initial 3-h treatments began within 30 min of life; three additional treatments were permitted within 48 h of life, based on clinical response, each being separated by at least 3 h in one group, and 1 h in another. Of the 17 infants studied, 11 were 30e32 weeks of gestation, and 6 were 28e29 weeks. Eleven (64%) infants required only the initial aerosol treatment, while one infant received four doses. The authors reported that transient desaturation during dosing was not associated with bradycardia or hypotension and the procedure was generally well tolerated.26 Only one infant developed CLD. This pilot trial is encouraging in establishing proof of concept and an acceptable safety profile and justifies the performance of a larger phase III trial. This could potentially revolutionise the way infants with or at risk for RDS are managed.
Research directions Compare the efficacy, safety, and long-term outcomes of CPAP versus surfactant and mechanical ventilation in extremely low birthweight infants. Define the population most in need of surfactant and mechanical ventilation, as well as the population most likely to be successfully managed by CPAP alone. Explore the efficacy and safety of aerosolised surfactant delivered by CPAP, and thus avoid intubation and mechanical ventilation.
References Conclusion The immediate respiratory management of the preterm baby with RDS remains controversial and prone to personal preference. It seems that CPAP might be a suitable alternative to intubation and ventilation for provision of respiratory support in a subgroup of preterm infants, who are relatively more mature and show adequate respiratory drive. However, the available data do not demonstrate sufficient efficacy and safety for its routine use as a primary treatment strategy in babies who are more premature. Future research in this area is needed to answer a number of clinically relevant shortand long-term questions. Although short-term data are useful, a full interpretation of their usefulness cannot be made in the absence of long-term follow-up data, such as general health status, respiratory function, and neurodevelopmental outcomes. Until then, clinicians should resist the temptation to use a device without evidence to support its use unless it is part of a clinical trial.
Practice points Infants born prematurely have underdeveloped lungs characterised by both morphological and biochemical abnormalities. Respiratory distress syndrome (RDS) is inversely proportional to gestational age, both in terms of frequency and severity. Surfactant replacement therapy has been established as a highly beneficial treatment for the prevention and treatment of RDS. Continuous positive airway pressure (CPAP) can successfully treat some preterm infants and avoid the risks of mechanical ventilation. Controversy still exists as to the best approach to treat preterm infants in the delivery room.
1. Sinha SK, Donn SM. Fetal-to-neonatal maladaptation. Semin Fetal Neonatal Med 2006;11:166e73. 2. Bhutani VK. Development of respiratory system. In: Donn SM, Sinha SK, editors. Manual of neonatal respiratory care. Philadelphia: Mosby Elsevier; 2006. p. 3e10. 3. Donn SM, Sinha SK. Minimising ventilator induced lung injury in preterm infants. Arch Dis Child Fetal Neonatal Ed 2006;91: F226e30. 4. Halamek LP, Morley C. Continuous positive airway pressure during neonatal resuscitation. Clin Perinatol 2006;33:83e98. 5. Yost CC, Soll RF. Early versus delayed selective surfactant treatment for neonatal respiratory distress syndrome. Cochrane Database Syst Rev 1999;(4):CD001456. 6. Sinha SK, Moya F, Donn SM. Surfactant for respiratory distress syndrome: are there important clinical differences among preparations? Curr Opin Pediatr 2007;19:150e4. 7. Moya F, Maturana A. Animal-derived surfactants versus past and current synthetic surfactants: current status. Clin Perinatol 2007;34:145e77. 8. Moya F, Sinha S, Gadzinowski J, et al. One-year follow-up of very preterm infants who received lucinactant for prevention of respiratory distress syndrome: results from 2 multicenter randomized, controlled trials. Pediatrics 2007;119:e1361e70. 9. Probyn ME, Hooper SB, Dargaville PA, et al. Positive end expiratory pressure during resuscitation of premature lambs rapidly improves blood gases without adversely affecting arterial pressure. Pediatr Res 2004;56:198e204. 10. Jobe AH, Kramer BW, Moss TJ, Newnham JP, Ikegami M. Decreased indicators of lung injury with continuous positive airway pressure in preterm lambs. Pediatr Res 2002;52:387e92. 11. Michna J, Jobe AH, Ikegami M. Positive end-expiratory pressure preserves surfactant function in preterm lambs. Am J Resp Crit Care Med 1999;160:634e9. 12. Mulrooney N, Champion Z, Moss TJ, Nitsos I, Ikegami M, Jobe AH. Surfactant and physiologic responses of preterm lambs to continuous positive airway pressure. Am J Respir Crit Care Med 2005;171:488e93. 13. Schlessel JS, Susskind H, Joel DD, et al. Effect of PEEP on regional ventilation and perfusion in mechanically ventilated preterm lamb. J Nucl Med 1989;30:1342e50. 14. Finer NN, Carlo WA, Duara S, et al. Delivery room continuous positive airway pressure/positive end expiratory pressure in extremely low birth weight infants: a feasibility trial. Pediatrics 2004;114:651e7. 15. Davis PG, Henderson-Smart DJ. Nasal continuous positive airways pressure immediately after extubation for preventing morbidity in preterm infants. Cochrane Database Syst Rev 2003;(2):CD000143.
Respiratory management of preterm infant 16. Avery ME, Tooley WH, Keller JB, et al. Is chronic lung disease in low birth weight infants preventable? A survey of eight centres. Pediatrics 1987;79:26e30. 17. Van Marter LJ, Allred EN, Pagano M, et al. Do clinical markers of barotraumas and oxygen toxicity explain interhospital variation in rates of chronic lung disease? Pediatrics 2000;105:119e201. 18. de Paoli AG, Morley C, Davis PG. Nasal CPAP for neonates: what do we know in 2003? Arch Dis Child Fetal Neonatal Ed 2003;88: 168e72. 19. Ammari A, Suri M, Milisavljevic V, et al. Variables associated with early failure of nasal CPAP in very low birth weight infants. J Pediatr 2005;147:341e7. 20. Verder H, Robertson B, Greisen G, et al. Surfactant therapy and nasal continuous positive airway pressure for newborns with respiratory distress syndrome. N Engl J Med 1994;331:1051e5. 21. Verder H, Albertsen P, Ebbesen F, et al. Nasal continuous positive airway pressure and early surfactant therapy for
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22.
23.
24.
25. 26.
respiratory distress syndrome in newborns of less than 30 weeks’ gestation. Pediatrics 1999;130:e24. Thomson MA. Early nasal CPAP þ prophylactic surfactant for neonates at risk of RDS. The IFDAS trial (abstract). Pediatr Res 2001;50:304A. Morley CJ, COIN trial collaborators. Nasal CPAP or ventilation for very preterm infants at birth: a randomised controlled trial e The COIN trial. E-PAS 2007;61:6090.1. Finer N. To intubate or not e that is the question: continuous positive airway pressure versus surfactant and extremely low birth weight infants. Arch Dis Child Fetal Neonatal Ed 2006; 91:F392e4. Mazela J, Merritt TA, Finer NN. Aerosolized surfactants. Curr Opin Pediatr 2007;19:155e62. Finer NN, Merritt TA, Bernstein G, Job L. A multicenter, pilot study of Aerosurf delivered via nasal CPAP to prevent RDS in pre-term neonates. EPAS 2006;59:4840.138.
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/siny
Immediate respiratory management of the preterm infant Sunil K. Sinha a,b,*, Samir Gupta b, Steven M. Donn c a
Paediatrics and Neonatal Medicine, University of Durham, Durham, UK The James Cook University Hospital, Middlesbrough TS4 3BW, UK c Department of Pediatrics, Division of Neonatal-Perinatal Medicine, University of Michigan Health System, C.S. Mott Children’s Hospital, Ann Arbor, MI 48103, USA b
KEYWORDS Chronic lung disease; Continuous positive airway pressure (CPAP); Prematurity; Respiratory distress syndrome (RDS); Surfactant
Summary Infants born prematurely have underdeveloped lungs characterised by both morphological and biochemical abnormalities. Respiratory distress syndrome (RDS) is the leading cause of morbidity and mortality in this population. Both surfactant replacement therapy with mechanical ventilation and continuous positive airway pressure (CPAP) have been shown to be of benefit. However, considerable controversy exists about how best to use these therapies. This paper will review the pathophysiology of RDS and the evidence supporting each of these treatments. ª 2007 Elsevier Ltd. All rights reserved.
Introduction Respiratory distress syndrome (RDS) is a disorder of the preterm lung and is a leading cause of death and pulmonary morbidity in babies born prematurely. The incidence and severity of RDS is inversely proportional to gestational age. RDS has both unique biochemical and morphological characteristics. Abnormalities in pulmonary histology and cytoarchitecture include insufficient alveolarisation, diminished functional surface area, an increased distance from the alveolus to its adjacent capillary, deposition of fibrin into the air spaces, and pulmonary arteriolar muscularinisation. The biochemical abnormality is the deficiency of surfactant, which leads to increased alveolar surface tension and collapse, progressive atelectasis and decreased * Corresponding author. Paediatrics and Neonatal Medicine, University of Durham, Durham, UK. E-mail address: [email protected] (S.K. Sinha).
pulmonary compliance. Affected infants frequently require mechanical ventilation and are at risk for ventilatorinduced lung injury, and 30e40% develop chronic lung disease (CLD), sometimes severe enough to interfere with normal growth and development.1 Respiratory maladaptation at birth can also result from a number of other causes, including an abnormal transition of the fetus from the intrauterine to extrauterine environment. The hallmark of normal transition is the conversion of the fluid-filled lungs into a hollow organ distended with air and capable of gaseous exchange sufficient to support life. The majority of babies born beyond 32 weeks of gestation will establish normal respiration without much help after delivery. However, the situation is different for infants born at an earlier gestational age because of the propensity to develop RDS. Any supportive care provided in the immediate neonatal period must be based on an understanding of the pathophysiology of these homeostatic mechanisms.
1744-165X/$ - see front matter ª 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.siny.2007.09.006
Respiratory management of preterm infant Human lung development goes through various stages including pseudoglandular (5e17 weeks), canalicular (16e 26 weeks), saccular (24e38 weeks) and finally alveolar (36 weeks to 2 years). During intrauterine development, the fetal lungs are filled with liquid secreted by the pulmonary epithelium. The volume and rate at which the liquid is secreted into the fetal lungs are calibrated to maintain lung volume at about functional residual capacity (FRC) and are the major determinants of normal lung growth. After birth, the pulmonary fluid is actively absorbed, and with introduction of air into the lungs, an air/liquid interface, facilitated by surfactant, forms the alveolar lining. The physical properties of the surfactant lining are such that the surface tension effect at the air/liquid interface is minimised, facilitating alveolar expansion and preventing the collapse of small alveoli, in accordance with LaPlace principle.2 Another important event is the transition from fetal respiratory activity to normal ventilation (establishing spontaneous breathing) soon after birth. During spontaneous breathing, the driving pressure required to overcome elastic, air-flow-resistive and inertial properties of the respiratory system is the result of intrapleural pressure (PIP) changes generated by the respiratory muscles. Factors that influence the respiratory muscles and respiratory mechanics have an effect on how air flows into and out of the lungs. The process of spontaneous breathing generally occurs at about one-third of total lung capacity, so that two-thirds of the total capacity is available as reserve. The capacity of the lungs can be represented in four different ways: total lung capacity, vital capacity, inspiratory capacity and functional residual capacity (FRC). FRC is the volume of gas in the lungs at the end of a normal expiration and is in continuity with the airways. A normal FRC enables optimal lung mechanics and alveolar surface area for efficient ventilation and gas exchange. The physiological processes that facilitate the onset of postnatal pulmonary gas exchange include: 1. The effect of ventilation on reducing pulmonary vascular resistance. 2. The effect of a more alkaline pH on reducing pulmonary vascular resistance to facilitate pulmonary blood flow. 3. Successful establishment of respiration to achieve an optimal FRC. 4. The effect of driving pressure to maintain optimal tidal volume. The majority of babies born at higher gestational ages will establish normal respiratory and circulatory function without help. However, a significant proportion of those who are born too early may experience difficulties in dealing with these normal adaptive processes and may die as a consequence, unless appropriately supported. Supportive treatments include exogenous surfactant replacement therapy (with attendant intubation and at least a brief period of positive pressure ventilation) and/or continuous positive airway pressure (CPAP). Some babies, particularly those born before 28 weeks of gestation, will still require assisted ventilation.
25
Current therapeutic options: how do they work? Pulmonary surfactant is a multicomponent compound of several phospholipids, neutral lipids and associated proteins. Of the phospholipids, dipalmitoyl phosphatidylcholine is the most prevalent component, with a structure that is well suited to form a stable monolayer required to generate the low surface tension to prevent alveolar collapse at end-expiration. Administration of exogenous surfactant to a surfactant-deficient preterm newborn decreases the minimum pressure required to open the lungs, increases the maximal lung volume, and prevents lung collapse at low pressure. These effects produce a hysteresis in surface tension versus surface area, allowing uniform expansion and contraction of normal alveoli. Instilling surfactant before the onset of RDS has been shown to partially avoid barotrauma and ventilator-induced lung injury resulting from mechanical ventilation.3 CPAP is positive pressure applied to the airways of a spontaneously breathing baby throughout the respiratory cycle. The rationale for use of CPAP is to support the airways and avoid alveolar collapse to a level below FRC. The premature baby has an immature lung structure with relatively undeveloped internal architecture to maintain lung volume, so that it is not held open by internal support. Moreover, the chest wall of the premature baby is soft and pliable, and thus not capable of holding the lung open during excessive inspiratory effort. Additionally, the pull of the diaphragm (and thus the negative pressure generated) distorts the chest wall and reduces the tidal volume. CPAP reduces the likelihood of upper airway collapse and decreases upper airway resistance by mechanically splinting it open. It increases the pharyngeal cross-sectional area and decreases genioglossus activity. CPAP also alters the shape of the diaphragm and increases its activity, improves lung compliance, and decreases airway resistance. This allows a greater tidal volume for a given negative pressure, with subsequent reduction in the work of breathing. CPAP also seems to conserve surfactant on the alveolar surface, and therefore may have a synergistic effect.4
Evidence of effectiveness Exogenous surfactant replacement therapy Surfactant therapy, whether used as treatment or prophylaxis, is well known to reduce morbidity and mortality in newborns with or at risk for RDS. Timing of surfactant administration, and to some extent, type of surfactant used, are important considerations. A meta-analysis compared the effect of early (less than 2 h) versus delayed rescue administration of surfactant therapy in infants intubated for RDS. The results demonstrated that early treatment significantly reduces the incidence of pneumothorax, pulmonary interstitial emphysema, CLD, and mortality compared to delayed treatment. This meta-analysis included one prevention trial (Exosurf versus Infasurf) and 10 treatment trials (seven trials comparing Exosurf with Survanta; one trial comparing Exosurf with Infasurf;
26 one trial comparing ALEC with Curosurf; and one trial comparing Curosurf with Exosurf). This review concluded that all types of surfactants are effective in the treatment and prevention of RDS, but suggested that use of animalderived surfactant resulted in fewer deaths (number needed to treat [NNT Z 37]), greater reduction in the level of ventilatory support, and a lower incidence of pneumothorax (NNT Z 20) compared to synthetic products, which do not contain the associated proteins.5 The beneficial effects of animal-derived surfactants were thought to be related to the protein content of these preparations. No reduction in the incidence of bronchopulmonary dysplasia (BPD) was reported in this review or in any of the individual trials included. Interpretation of the findings of this meta-analysis, however, should be viewed with caution, as the studies included were quite heterogeneous in population characteristics, entry criteria and primary outcomes. Many of these trials were not blinded, while the surfactants used in these trials also differed in their key components, volume of administration and dose of phospholipids. It is quite possible that the advantages attributed to the animal-derived surfactants in this metaanalysis might have been inadvertently exaggerated.6,7 More recently, newer synthetic surfactants have been developed. One of these is Surfaxin, a synthetic surfactant containing an artificial peptide (Sinapultide), which mimics the biological properties of human surfactant protein B. Surfaxin was found to be as good as, if not superior to, currently available animal-derived surfactants.8
CPAP and resuscitation The data from animal studies suggest that providing positive end-expiratory pressure (PEEP) during resuscitation reduces the alveolar-arterial oxygen gradient proportional to the level of PEEP applied,9 lowers indicators of acute lung injury,10 improves alveolar surfactant pool size,11 and improves oxygenation12 and ventilation/perfusion matching.13 Both observational and cohort studies have examined CPAP use after initial resuscitation in the delivery room as a treatment for RDS. They have consistently shown that it is feasible to use CPAP in a select group of infants with reduction in the need for mechanical ventilation. The only randomised controlled trial (RCT) during resuscitation was a pilot trial reported by Finer et al., who randomised 104 infants <28 weeks of gestation to CPAP or no positive pressure after delivery. Only 4 of the 43 infants weighing <700 g and 3 of the 37 infants <25 weeks of gestation were able to be resuscitated successfully with CPAP alone; overall, 80% of study infants had to be intubated within the first 7 days of life. The result of this study confirms the impression that CPAP alone is unlikely to succeed in this cohort of very immature infants.14
CPAP and RDS Although there is no doubt that use of CPAP post-extubation is beneficial and helps to reduce extubation failure after positive pressure ventilation,15 it still remains a moot point whether early use of CPAP, starting at birth, has the same
S.K. Sinha et al. benefit in terms of patient outcomes. The stimulus to use CPAP at birth as a mode of support for very low birthweight infants comes from an observation by Avery et al.,16 subsequently confirmed by Van Marter et al.,17 who did a retrospective review of contemporary practices and clinical outcomes in a number of neonatal units in the USA. They observed a significantly lower incidence of CLD in a unit at Columbia University, which had a much greater use of CPAP compared to the others who used mainly intubation and mechanical ventilation as a primary treatment strategy. The unit also used markedly less surfactant (10% versus 45%), and yet was able to maintain a low rate of CLD compared to the other regional centres. Interestingly, this observation also found that the use of mechanical ventilation on day 1 increased the odds of developing CLD 13fold, with a decreasing odds ratio associated with initiation of mechanical ventilation later in the first week of life. These practices, however, preceded the ‘surfactant era’ at a time when the use of antenatal corticosteroids was also low. Coincident with development of exogenous surfactant therapy, interest in primary CPAP therapy waned. Since then, however, there has been a resurgence of interest in CPAP, so much so that it is now becoming a common practice in many neonatal units despite a lack of clear evidence of its efficacy and safety. We also do not know what group of babies is most likely to benefit from early CPAP treatment, what level of CPAP is safe, what device to use e fixed flow versus variable flow e and whether CPAP’s short-term benefit is maintained, as there are no longterm follow-up data available.18 The recent experience from Columbia University has been presented in more depth by Ammari et al.19 who reviewed the courses of 261 infants <1250 g and reported their outcomes at 72 h of age based on the initial respiratory support modality. The researchers divided the infants into two groups: (1) CPAP-started group; and (2) ventilatorstarted group. The CPAP group was further subdivided into ‘CPAP success’ or ‘CPAP failure’. They observed that infants who succeeded on CPAP were about 3 weeks more mature and weighed about 300 g more than those who failed CPAP therapy (p < 0.001). The ventilator-started infants were about 30 times more likely to have received positive pressure via bag and mask at delivery than infants who were started on CPAP (91% versus 24%; OR Z 29.9; 95% CI 8.8, 102). Death occurred in 21/32 (66%) ventilator-started infants compared to only 20/229 (9%) CPAP-started infants. Mortality in the CPAP failure group was 18/55 (33%), and mortality in the CPAP success group was 2/174 (1%). However, such data have to be interpreted with caution because the differences might be influenced by a variety of factors, including condition at birth and severity of lung disease. Notably, only 51% of the infants who were CPAP failures and 53% of infants ventilated from birth received surfactant. Withholding surfactant treatment in such cases might have contributed to both mortality and morbidity and cannot be evaluated because of incomplete patient details.
Combination therapy: surfactant and CPAP There are limited data on the combined use of CPAP and surfactant immediately after birth. Verder et al.20
Respiratory management of preterm infant reported an RCT of infants with moderate-to-severe surfactant deficiency treated with nasal CPAP and a single dose of Curosurf given during a brief period of intubation. This significantly reduced the need for subsequent mechanical ventilation during the first 7 days. The study was criticised because babies >30 weeks were included and treatment was given late (median age 12 h). In a subsequent RCT,21 these investigators confined enrolment to babies <30 weeks of gestation and reported that the combined use of early CPAP with earlier administration of Curosurf resulted in a significant reduction in the need for mechanical ventilation. In both of these trials, there were no differences in death or BPD when compared to the control group. Although it proved the superiority of combining surfactant with CPAP compared to CPAP alone, it did not answer the question of whether early CPAP and surfactant is better than mechanical ventilation following surfactant administration. In another multicentre RCT, Thomson22 randomised infants into four groups: (1) early CPAP with prophylactic surfactant; (2) early CPAP with rescue surfactant; (3) early mechanical ventilation (intermittent positive pressure ventilation [IPPV]) with prophylactic surfactant; and (4) conventional management, with rescue IPPV and rescue surfactant treatment, if needed. There was no difference in the total respiratory support (mechanical ventilation and CPAP) until discharge or CLD among the groups. This study confirmed the observation that CPAP, with or without prophylactic surfactant, reduces the need for mechanical ventilation when applied as the initial respiratory support. This study, however, excluded babies <27 weeks, who are the most vulnerable group. To date, there have been no prospective studies comparing the use of early CPAP versus prophylactic or early surfactant in the extremely premature and most vulnerable infants. Although individual units report their successes with early CPAP in very low birthweight infants, the use and timing of surfactant administration in such infants, either before the use of CPAP or for infants who failed CPAP, have not been consistently reported. This underscores the need for an RCT of early CPAP versus the most evidence-based intervention, prophylactic or early surfactant.
On the horizon So far, most of the information on the early use of CPAP has come from retrospective cohort studies, but results of RCTs have started to appear, which should provide a better level of evidence. One such study, recently published in abstract form is the COIN trial.23 This trial examined the feasibility of early CPAP in babies <29 weeks of gestation in a multicentre RCT, in which 610 preterm babies 25e28 weeks of gestation were randomised to receive either CPAP (8 cm H2O) or intubation and ventilation immediately after birth. A third of the enrolled babies were 25e26 weeks of gestation. At 28 days postnatal age, the CPAP group had fewer deaths or need for supplemental oxygen (OR Z 0.63; 95% CI 0.46, 0.86; p Z 0.006). This advantage was, however, lost at 36 weeks of PMA. The intubation rate in the first 5 days for the CPAP group was 46% (55%
27 for 25e26 weeks and 40% for 27e28 weeks). There were no significant difference in the duration of respiratory support or the incidence of complications related to prematurity, but there was a significant increase in the rate of pneumothorax in the CPAP group (9% versus 3%). Although this trial showed that babies aged 25e28 weeks, who breathe spontaneously at birth, can be successfully managed with early CPAP, the denominator of the total number of preterm infants between 25 and 28 weeks of gestation requiring respiratory support at birth during the study period was not provided and thus it is difficult to extrapolate the findings to the general population of extremely preterm babies. There are at least two further ongoing RCTs on nasal CPAP, which should provide some useful information when completed.24 The VermonteOxford Network is now enrolling infants in a 3-armed trial in which infants born at 26e29 weeks of gestation are being randomised after 6 days to one of three groups: (1) intubation, early prophylactic surfactant, and subsequent stabilisation on mechanical ventilation; (2) intubation, early prophylactic surfactant, and rapid extubation to CPAP; and (3) early stabilisation with nasal CPAP, with selective intubation and surfactant administration according to clinical guidelines. This trial is also not recruiting infants <26 weeks, which will leave the question about what to do with the most vulnerable group unanswered (http://www.vtoxford.org/home.aspx?pZ research/drm/index.htm). Another trial (SUPPORT) is currently enrolling infants of 24e27 weeks of gestation and randomising to either CPAP beginning in the delivery room with criteria for subsequent intubation, or intubation with surfactant treatment within 1 h of birth with continuing mechanical ventilation.
Aerosolised surfactant The usefulness of exogenous surfactant therapy, either given prophylactically or as a rescue therapy, for both prevention and treatment of RDS, is well established. However, the administration of surfactant requires endotracheal intubation, which is not a benign procedure. If surfactant could be delivered by CPAP, as an aerosol, an effective compromise might be reached. Clinical studies for the treatment and prophylaxis of newborns with RDS have suggested the safety of this approach, but the results of these studies have been contradictory. In order to be successful, the surfactant would have to survive the aerosolisation process, be able to be delivered to the distal portions of the lung, reaggregate, and maintain biological activity. The method of delivery is also important as, hypothetically, the most efficient aerosolised surfactant system should use an aerosol flow equal or close to peak inspiratory flow (PIF) or a volume of aerosol equal to minute ventilation to avoid dilution.25 A recent clinical study with aerosolised lucinactant (Aerosurf) has shown the feasibility and safety of delivering this synthetic peptide-containing surfactant to newborns with early signs of RDS. In this pilot study, a vibrating membrane nebuliser (Aeroneb Pro, Artemis
28
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Med, UK) was used to aerosolise 20 mg/mL Aerosurf. Initial 3-h treatments began within 30 min of life; three additional treatments were permitted within 48 h of life, based on clinical response, each being separated by at least 3 h in one group, and 1 h in another. Of the 17 infants studied, 11 were 30e32 weeks of gestation, and 6 were 28e29 weeks. Eleven (64%) infants required only the initial aerosol treatment, while one infant received four doses. The authors reported that transient desaturation during dosing was not associated with bradycardia or hypotension and the procedure was generally well tolerated.26 Only one infant developed CLD. This pilot trial is encouraging in establishing proof of concept and an acceptable safety profile and justifies the performance of a larger phase III trial. This could potentially revolutionise the way infants with or at risk for RDS are managed.
Research directions Compare the efficacy, safety, and long-term outcomes of CPAP versus surfactant and mechanical ventilation in extremely low birthweight infants. Define the population most in need of surfactant and mechanical ventilation, as well as the population most likely to be successfully managed by CPAP alone. Explore the efficacy and safety of aerosolised surfactant delivered by CPAP, and thus avoid intubation and mechanical ventilation.
References Conclusion The immediate respiratory management of the preterm baby with RDS remains controversial and prone to personal preference. It seems that CPAP might be a suitable alternative to intubation and ventilation for provision of respiratory support in a subgroup of preterm infants, who are relatively more mature and show adequate respiratory drive. However, the available data do not demonstrate sufficient efficacy and safety for its routine use as a primary treatment strategy in babies who are more premature. Future research in this area is needed to answer a number of clinically relevant shortand long-term questions. Although short-term data are useful, a full interpretation of their usefulness cannot be made in the absence of long-term follow-up data, such as general health status, respiratory function, and neurodevelopmental outcomes. Until then, clinicians should resist the temptation to use a device without evidence to support its use unless it is part of a clinical trial.
Practice points Infants born prematurely have underdeveloped lungs characterised by both morphological and biochemical abnormalities. Respiratory distress syndrome (RDS) is inversely proportional to gestational age, both in terms of frequency and severity. Surfactant replacement therapy has been established as a highly beneficial treatment for the prevention and treatment of RDS. Continuous positive airway pressure (CPAP) can successfully treat some preterm infants and avoid the risks of mechanical ventilation. Controversy still exists as to the best approach to treat preterm infants in the delivery room.
1. Sinha SK, Donn SM. Fetal-to-neonatal maladaptation. Semin Fetal Neonatal Med 2006;11:166e73. 2. Bhutani VK. Development of respiratory system. In: Donn SM, Sinha SK, editors. Manual of neonatal respiratory care. Philadelphia: Mosby Elsevier; 2006. p. 3e10. 3. Donn SM, Sinha SK. Minimising ventilator induced lung injury in preterm infants. Arch Dis Child Fetal Neonatal Ed 2006;91: F226e30. 4. Halamek LP, Morley C. Continuous positive airway pressure during neonatal resuscitation. Clin Perinatol 2006;33:83e98. 5. Yost CC, Soll RF. Early versus delayed selective surfactant treatment for neonatal respiratory distress syndrome. Cochrane Database Syst Rev 1999;(4):CD001456. 6. Sinha SK, Moya F, Donn SM. Surfactant for respiratory distress syndrome: are there important clinical differences among preparations? Curr Opin Pediatr 2007;19:150e4. 7. Moya F, Maturana A. Animal-derived surfactants versus past and current synthetic surfactants: current status. Clin Perinatol 2007;34:145e77. 8. Moya F, Sinha S, Gadzinowski J, et al. One-year follow-up of very preterm infants who received lucinactant for prevention of respiratory distress syndrome: results from 2 multicenter randomized, controlled trials. Pediatrics 2007;119:e1361e70. 9. Probyn ME, Hooper SB, Dargaville PA, et al. Positive end expiratory pressure during resuscitation of premature lambs rapidly improves blood gases without adversely affecting arterial pressure. Pediatr Res 2004;56:198e204. 10. Jobe AH, Kramer BW, Moss TJ, Newnham JP, Ikegami M. Decreased indicators of lung injury with continuous positive airway pressure in preterm lambs. Pediatr Res 2002;52:387e92. 11. Michna J, Jobe AH, Ikegami M. Positive end-expiratory pressure preserves surfactant function in preterm lambs. Am J Resp Crit Care Med 1999;160:634e9. 12. Mulrooney N, Champion Z, Moss TJ, Nitsos I, Ikegami M, Jobe AH. Surfactant and physiologic responses of preterm lambs to continuous positive airway pressure. Am J Respir Crit Care Med 2005;171:488e93. 13. Schlessel JS, Susskind H, Joel DD, et al. Effect of PEEP on regional ventilation and perfusion in mechanically ventilated preterm lamb. J Nucl Med 1989;30:1342e50. 14. Finer NN, Carlo WA, Duara S, et al. Delivery room continuous positive airway pressure/positive end expiratory pressure in extremely low birth weight infants: a feasibility trial. Pediatrics 2004;114:651e7. 15. Davis PG, Henderson-Smart DJ. Nasal continuous positive airways pressure immediately after extubation for preventing morbidity in preterm infants. Cochrane Database Syst Rev 2003;(2):CD000143.
Respiratory management of preterm infant 16. Avery ME, Tooley WH, Keller JB, et al. Is chronic lung disease in low birth weight infants preventable? A survey of eight centres. Pediatrics 1987;79:26e30. 17. Van Marter LJ, Allred EN, Pagano M, et al. Do clinical markers of barotraumas and oxygen toxicity explain interhospital variation in rates of chronic lung disease? Pediatrics 2000;105:119e201. 18. de Paoli AG, Morley C, Davis PG. Nasal CPAP for neonates: what do we know in 2003? Arch Dis Child Fetal Neonatal Ed 2003;88: 168e72. 19. Ammari A, Suri M, Milisavljevic V, et al. Variables associated with early failure of nasal CPAP in very low birth weight infants. J Pediatr 2005;147:341e7. 20. Verder H, Robertson B, Greisen G, et al. Surfactant therapy and nasal continuous positive airway pressure for newborns with respiratory distress syndrome. N Engl J Med 1994;331:1051e5. 21. Verder H, Albertsen P, Ebbesen F, et al. Nasal continuous positive airway pressure and early surfactant therapy for
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respiratory distress syndrome in newborns of less than 30 weeks’ gestation. Pediatrics 1999;130:e24. Thomson MA. Early nasal CPAP þ prophylactic surfactant for neonates at risk of RDS. The IFDAS trial (abstract). Pediatr Res 2001;50:304A. Morley CJ, COIN trial collaborators. Nasal CPAP or ventilation for very preterm infants at birth: a randomised controlled trial e The COIN trial. E-PAS 2007;61:6090.1. Finer N. To intubate or not e that is the question: continuous positive airway pressure versus surfactant and extremely low birth weight infants. Arch Dis Child Fetal Neonatal Ed 2006; 91:F392e4. Mazela J, Merritt TA, Finer NN. Aerosolized surfactants. Curr Opin Pediatr 2007;19:155e62. Finer NN, Merritt TA, Bernstein G, Job L. A multicenter, pilot study of Aerosurf delivered via nasal CPAP to prevent RDS in pre-term neonates. EPAS 2006;59:4840.138.