04/05/2005
EARLY NASAL CONTINUOUS POSITIVE AIRWAY PRESSURE AND SURFACTANT. A POTENTIAL COMBINATION THERAPY TO REDUCE BPD
Part 1. The evidence

Merran A Thomson
Department of Paediatrics and Neonatal Medicine Queen Charlotte’s and Chelsea Hospital at the Hammersmith Hospital, London - United Kingdom

Introduction
This 2 part article discusses first the evidence to support the use of early nCPAP combined with surfactant in the extremely preterm infant. The second part will detail the current clinical practices that have been adopted in our institution in an attempt to reduce bronchopulomonary dysplasia (BPD) in extremely preterm infants.

When Northway [1] first described BPD in 1967 little was known about the injurious effects of ventilation and oxygen. Today despite the numerous pharmacological and technical advances in neonatal lung care, BPD remains a cause of serious morbidity in surviving preterm infants. This “new BPD” differs from that originally described by Northway in that it affects predominantly those infants born between 24 and 28 weeks gestation with birth weights less than 1000 grams, many of whom will have received antenatal glucocorticoids, minimal ‘gentle ventilation’, and exogenous surfactant therapy [2].

A variety of factors including surfactant deficiency, volutrauma, oxygen exposure, antenatal exposure to pro-inflammatory cytokines, postnatal infection, patent ductus arteriosus and inadequate postnatal nutrition, are thought to play a role in the pathogenesis of neonatal BPD. The single greatest predictor for BPD appears to be the initiation of mechanical ventilation in the very low birthweight infant [3-5].

The introduction of more complex ventilatory strategies such as high frequency oscillatory ventilation (HFOV) [6], patient trigger [7] and volume techniques have not been associated with a reduction in the incidence of BPD in extremely preterm babies. Long term animal studies demonstrate that HFOV reduces the severity of lung injury but does not prevent the arrest in alveolarization and vascular development which underlies new BPD [8-10]. This failure may be due to the fact that all respiratory support strategies which involve endotracheal intubation for any length of time expose the susceptible lungs of the preterm infant to both ventilatory induced injury (baro and volu-trauma) and low grade infection of the lung parenchyma. The associated inflammation then contributes to the development of BPD.

Can early nCPAP help?

The development of ventilation and oxygen exposure strategies that minimize lung injury should improve the outcome of the extremely preterm infant. However preterm infants who fail to achieve a functional residual capacity (FRC) are more likely to develop hyaline membrane disease [11]. The best way to avoid mechanical ventilation could be to use nCPAP whenever possible, thereby minimising volutrauma yet intervening to prevent atelectasis and the cycle of events that lead to acute lung injury, inflammation and increased risk of BPD. Avoidance of intubation would prevent the reduction of mucociliary flow, mucosal injury and secondary infection.

How does nCPAP work?

nCPAP’s mechanism of action is complex and only partially understood. It is believed to work by improving oxygenation without increasing PaCO2 through the stabilisation and then recruitment of collapsed alveoli. The FRC is increased, resulting in an increased alveolar surface area for gas exchange and a decrease in intrapulmonary shunt. Endogenous surfactant is conserved. The breathing pattern regularises with stabilisation of the rib cage, reduced recession and increased efficiency of the diaphragm [12].

What is the evidence to support the use of early nCPAP?

a. Retrospective evidence
In 1987, Avery [4] suggested that the lower rate of chronic lung disease seen in certain units may be due to a combination of factors including the use of early CPAP and permissive hypercapnia. Few randomised controlled trials have evaluated the role of CPAP; most were undertaken in the pre surfactant and antenatal steroid era (1970’s to 1980’s) using a variety of methods. Small trials have compared CPAP vs. no CPAP, and early vs. late CPAP for the treatment of respiratory distress syndrome (RDS). A review of prophylactic CPAP published by The Cochrane Library [13] concluded that these few small trials provided insufficient information to make recommendations for clinical practice.

There was therefore little evidence to support the routine use of CPAP in infants with or at risk of developing RDS. During the early 1990’s uncontrolled retrospective studies from Denmark reported favourable survival outcomes with low BPD rates when preterm infants were treated with early nCPAP [14,15,16]. Similar retrospectives studies have now been published by many centres world wide [17,18] they report lower rates of BPD in units that avoid intubation and ventilation of preterm infants however none had undertaken formal randomised control trials.

The use of early nCPAP was not uniform in these retrospective studies; many differences exist including the age treatment was commenced, gestational age of infants included and the methods used to administer nCPAP. Given the porosity of data, what other evidence exists to support the current view that the use of early nCPAP in extremely preterm infants will have a beneficial effect on pulmonary outcome?

b. Animal evidence
Until very recently preterm animal models of RDS treated with early nCPAP had proved impossible to develop primarily due to poor respiratory drive. However recent studies have proved more successful and encouraging data has been published. Jobe and coworkers [19] documented in a two hour study that conventionally ventilated preterm lambs have significantly more neutrophils and hydrogen peroxide in alveolar washes than those lambs treated with CPAP indicating nCPAP administered from birth reduced the initial acute lung injury associated with mechanical ventilation. A longer term study in preterm baboons delivered at the equivalence of 25 weeks gestational age has shown that early nCPAP combined with prophylactic surfactant enables lung development to continue at a very similar rate to that in utero [20].

Do extremely preterm infants breathe if placed on nCPAP at birth?

The reports from neonatal units experienced in the technique of early nCPAP administered at birth suggest they can; with intubation in the delivery room reduced from 84% to 40% in a retrospective study of extremely low birthweight (ELBW) infants [21] and 89% to 33% in another [22]. However published work suggests there is a learning curve [22] and success is gestational age dependent. Almost all born at 24 weeks gestation or less required intubation in the delivery room however by 28 weeks the majority did not [21]. Some infants will require subsequent ventilation following initial nCPAP for worsening respiratory failure. These small retrospective studies also suggest a reduction in surfactant usage, number of days ventilated, BPD and length of stay. Adverse events such as intraventicular haemorrhage, necrotising enterocolitis and ROP were not increased.

Retrospective studies can not answer fully safety and efficacy issues. A recent 5 centre feasibility study has been published [23] which randomised 104 ELBW infants to receive either resuscitation with CPAP in the delivery room or if intubation was required PPV+PEEP; or PPV without PEEP only if intubation was required; once admitted to the neonatal unit all could receive nCPAP. In this study similar numbers required intubation in the deliver room (49% vs 41%) The authors state the overall rate of 45% was better than the 71% for infants <28 weeks gestation reported by the NICHD Neonatal Research Network for 2002. Gestational age and birthweight were both shown to determine the likelihood of intubation at delivery with 100% at 23 weeks, 53% at 24 weeks, 38% at 25 weeks, and 18% at 27 weeks (Figure 1); 9 out of 14 babies below 600g requiring intubation at delivery. An additional 35% of all infants required intubation within the first 7 days. The administration of CPAP/PEEP in the delivery room did not affect the need for intubation and ventilation either at delivery or in the first 7 days of life. In all only 20% of ELBW infants managed on nCPAP during their first 7 days of life. The study contains no data on safety or long term outcomes; the results have however been used to help in the design of the protocol for the SUPPORT trial which will compare the use of early nCPAP and a permissive ventilatory strategy at delivery and early surfactant followed by conventional ventilation in infants 24 to 27 weeks gestation. The results of this prospective randomised trial together with those from the COIN trial, and the Vermont Oxford Network nCPAP trial will help clarify the role early nCPAP has in the respiratory management of extremely preterm infants and the prevention of BPD.

Prophylactic nCPAP in the more mature infant

As already discussed most published nCPAP studies have been retrospective in nature however Sandri et al [24] have recently published a prospective randomised trial evaluating the benefits and risks of prophylactic nCPAP in infants of 28-31 weeks gestation. Infants were randomised to commence nCPAP either within 30 minutes of birth or if FiO2 exceeded 0.4. There was no difference in the need for surfactant or subsequent mechanical ventilation in the 2 groups and the authors conclude there is no benefit from commencing nCPAP prophylacticaly in these more mature infants.

The administration of surfactant in combination with nCPAP

Failure of early nCPAP can result from surfactant deficiency; nCPAP alone is unable to achieve a FRC, respiratory failure becomes established and ventilation with surfactant treatment is required. It is difficult to assess the surfactant pool required to enable an extremely preterm infant to establish stable respiration on nCPAP. However such studies can be preformed in animals. Mulrooney et al [25] reported that in the preterm lambs nCPAP failure was caused primarily by low surfactant pool size and that increased nCPAP pressure did not prevent failure. The administration of surfactant prophylacticaly may therefore be beneficial, increasing the likelihood of successful management on early nCPAP.

In 1994 Verder [26] reported in a randomised control trial that a single dose of surfactant (Curosurf™) given during a brief intubation significantly reduced the need for mechanical ventilation and improved oxygenation in infants with moderate to severe RDS who had been treated with early nCPAP. No significant differences were noted in the incidence of death, intracerebral haemorrhage, pneumothorax, or oxygen requirement at 28 days. This study was criticised as babies above 30 weeks gestation were included, and surfactant treatment was given late, median age of randomisation being 12 hours. In a subsequent controlled trial [27] confined to infants <30 weeks gestation the combined use of early nCPAP with the earlier administration of Curosurf™ resulted in a significant improvement in oxygenation and a further reduction in the need for mechanical ventilation. Again there were no differences for death or BPD.

Both of these studies recruited only those babies managed on nCPAP from soon after birth. They do not answer the question – is early nCPAP and surfactant treatment with addition of rescue ventilation if respiratory failure develops better than modern elective ventilation?

Two randomised controlled trials have attempted to answer this question. The first aimed to establish if early nCPAP with prophylactic surfactant was an effective and safe way to manage infants with or at risk of developing RDS [28]. 237 infants 27-29 weeks were randomised before birth to one of 4 treatment arms, early nCPAP with prophylactic surfactant, early nCPAP +/- rescue surfactant, early IPPV with prophylactic surfactant, and conventional management, (IPPV +/- rescue surfactant). 78% of infants in nCPAP groups were established on nCPAP by 6 hours of age (p<0.001), the majority by 2 hours of age. Increasing gestational age increased the probability of success (p<0.001). The early nCPAP groups had a reduced need for ventilation in the first 5 days of life however no treatment strategy reduced total duration of respiratory support, oxygen dependency at 28 days or 36 weeks. The need for further doses of surfactant was least in the early nCPAP with prophylactic surfactant group. nCPAP alone or combined with prophylactic surfactant were safe treatments with no differences in the rates of respiratory, ultrasound and other neonatal complications when compared to conventional management.

The second study [29] randomized 42 infants, 25–28 weeks, to either prophylactic surfactant and early extubation to nCPAP or prophylactic surfactant and continued ventilation. 8/21 (38%) randomised to nCPAP following surfactant did not require subsequent ventilation. Fewer babies in nCPAP group were ventilated at 72hrs (47% vs. 81% p=0.003) and they required less total days of ventilation (3days vs.7days p=0.01). No differences in mortality, BPD and IVH were noted.

Summary of current evidence

Early nCPAP offers the potential to reduce BPD in extremely preterm infants. However evidence to support its wide spread application is limited but encouraging. Many questions remain unanswered including:

• Which infants will breathe spontaneously soon after birth and are therefore candidates for early nCPAP?
• Will the early administration of surfactant either prophylacticaly or as early rescue increase the likelihood of success?
• Will early nCPAP be shown to reduce BPD within the setting of a randomised control trial?

Neonatologists wishing to introduce the technique of early nCPAP to their neonatal unit should recognise that although the device is simple, achieving success requires changes to the way many aspects of care are delivered by the multidisciplinary neonatal team. The “learning curve” can be challenging but may be helped by the participation of the neonatal unit in a randomised control trial. In the second part of this article I will discuss the clinical practises we adopted in 2001 which have resulted in an overall reduction in the amount of mechanical ventilation use in our neonatal unit (Figure 2).

References

1. Northway W, Rosan R, Porter D. Pulmonary disease following respirator therapy of hyaline membrane disease: bronchopulmonary dysplasia. N Engl J Med 1967;276:357–368.
2. Jobe A, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001;163:1723–1729 (Free Full Text).
3. Young T, Kruyer L, Marshall D, Bose C, North Carolina Neonatalogists Association. Population-based study of chronic lung disease in very low birth weight infants in North Carolina in 1994 with comparisons with 1984. Pediatrics 1999;104:e17 (Free Full Text).
4. Avery M, Tooley W, Keller J, Hurd S, Bryan M, Cotton R, Epstein M, Fitzhardinge P, Hansen C, Hansen T, Hodson W, James L, Kitterman J, Nielsen H, Poirier T, Truog W, Wung J-T. Is chronic lung disease in low birth weight infants preventable? A survey of eight centers. Pediatrics 1987;79:26–30 (PubMed).
5. Van Marter L, Allred E, Pagano M, Sanocka U, Parad R, Moore M, Susser M, Paneth N, Leviton A. Do clinical markers of barotrauma and oxygen toxicity explain interhospital variation in rates of chronic lung disease? Pediatrics 2000;105:1194–1201 (Free Full Text).
6. Henderson-Smart DJ, Bhuta T, Cools F, Offringa M. Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants. The Cochrane Database of Systematic Reviews 2003, Issue 4.
   Greenough A, Milner AD, Dimitriou G. Synchronized mechanical ventilation for respiratory support in newborn infants. The Cochrane Database of Systematic Reviews 2004, Issue 3.
7. Yoder BA, Siler-Khodr T, Winter VT, Coalson JJ. High-frequency oscillatory ventilation: effects on lung function, mechanics, and airway cytokines in the immature baboon model for neonatal chronic lung disease. Am J Respir Crit Care Med 2000;162:1867–1876 (Free Full Text).
8. Coalson JJ, Seidner SR, deLemos RA. Animal models of chronic lung injury. In: Bland RD, Coalson JJ, editors. Chronic lung disease in early infancy. New York: Marcel Dekker; 2000. p. 927–956.
9. Coalson J, Winter V, Siler-Khodr T, Yoder B. Neonatal chronic lung disease in extremely immature baboons. Am J Respir Crit Care Med 1999;160:1333–1346 (Free Full Text).
10. Upton CJ, Milner AD. Endotracheal resuscitation of neonates using a rebreathing bag. Arch Dis Child 1991;66:39-42 (PubMed).
11. Ahmuada CA, Goldsmith JP: Continuous distending pressure; in Goldsmith JP, Karotkin EH (eds): Assited Ventilation of the Neonate, ed 3. Philadelphia, Sanders, 1996, 151-165.
12. Subrananiam P, Henderson –Smart DJ, Davies PG. Prophylactic nasal continuous positive airways pressure for preventing morbidity and mortality in very preterm infants. The Cochrane Library, Issue 3, 2001
13. Kamper J, Wulff K, Larsen C, Lindequist S: Early treatment with nasal continuous positive airway pressure in very low birthweight infants. Acta Paediatr. 1993;82:193-197 (PubMed).
14. Jacobsen T, Grønvall J, Petersen S, Andersen GE: ‘Minitouch treatment of very low birthweight infants. Acta Paediatr. 1993;82:934-938 (PubMed).
15. Lundstrøm KE, Greisen G: Early treatment with early CPAP. Acta Paediatr. 1993;82:856.
16. Van Marter L, Allred E, Pagano M, Sanocka U, Parad R, Moore M, Susser M, Paneth N, Leviton A. Do clinical markers of barotrauma and oxygen toxicity explain interhospital variation in rates of chronic lung disease? Pediatrics 2000;105:1194–1201 (Free Full Text).
17. de Klerk AM, de Klerk RK. Nasal continuous positive airway pressure and outcomes in preterm infants. J Paediatr Child Health 2001;37:161-167 (PubMed).
18. Jobe AH, Kramer BW, Moss TJ, Newnham JP, Ikegami M. Decreased indicators of lung injury with continuous positive expiratory pressure in preterm lambs. Pediatric Research 2002;52:387-392 (Free Full Text).
19. Thomson MA, Yoder BA, Winter VT, Martin H, Catland D, Siler-Khoder TM, Coalson JJ. Treatment of immature baboons for 28 days with early nasal continuous positive airway pressure. Am J Respir Crit Care Med 2004;169:1054-1062 (Free Full Text).
20. Linder W, Vobbeck S, Hummler H, Pohlandt F. Delivery room management of extremely low birth weight infants: Spontaneous breathing or intubation. Pediatrics 1999;103:961-967 (Free Full Text).
21. Aly H, Milner JD, Patel K, El-Mohandes AAE. Does the experience with the use of nasal continuous positive airway pressure improve over time in extremely low birth weight infants? Pediatrics 2004;114:697-702 (PubMed).
22. Finer NN, Carlo WA, Duara S, Franaroff AA, Donovan EF, Wright LL, Kandefer S, Poole WF. Delivery room continuous positive airway pressure/positive end-expiratory pressure in extremely low birth weight infants: a feasibility trial. Pediatrics 2004;114:651-657 (PubMed).
23. Sandi F, Ancora G, Lanzoni A, Tagliabue P, Colnaghi M, Ventura ML, Rinaldi M, Mondello I, Gancia P, Salvioli GP, Orzalesi M, Mosco F. Prophylactic nasal continuous positive airway pressure in newborns of 28-31 weeks gestation: multicentre randomised contrlled clinical trial. Arch Dis Child Fetal Neontal Ed 2004;89:F394-F398.
24. Mulrooney N, Champion Z, Moss TJM, Nitsos I, Ikegami M, Jobe AH. Surfactant and physiological responses of preterm lambs to continuous positive airway pressure. Am J Respir Crit Care Med (in press).
25. Verder H, Robertson B, Greisen G, Ebbesen F, Albertsen P, Lundstrøm KE, Jacobson T. Surfactant therapy and nasal continuous positive airway pressure for newborns with respiratory distress syndrome. N Engl J Med 1994;331:1051-1055 (Free Full Text).
26. Verder H, Albertsen P, Ebbesen F, Greisen G, Robertson B, Bertelsen A, Agertoft L, Djernes B, Nathan E, Reinholdt J. Nasal continuous positive airway pressure and early surfactant therapy and for respiratory distress syndrome in newborns of less than 30 weeks’ gestation. Pediatrics 1999;130(2):e24
27. Thomson M. Early continuous positive airway pressure (nCPAP) with prophylactic surfactant for neonates at risk of RDS. The IFDAS multicentre randomized trial. Ped Research 2002;51:379A.
28. Tooley J, Dyke M. Randomised study of nasal continuous positive airway pressure in the preterm infant with respiratory distress syndrome. Acta Paediatr 2003 Oct; 92 (10): 1170-4 (PubMed).

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