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Published online by Cambridge University Press:  01 August 2008

King's College London School of Medicine, Denmark Hill, London
King's College London School of Medicine, Denmark Hill, London
Professor A Greenough, Professor of Clinical Respiratory Physiology, Newborn Unit, 4th Floor, Golden Jubilee Wing, King's College Hospital, London SE5 9RS.


Respiratory Distress Syndrome (RDS) is due to immaturity of the lungs, primarily the surfactant synthesising system; hence, the risk of RDS is inversely proportional to gestational age. The incidence of RDS has been reduced by the routine use of both antenatal corticosteroids and postnatal surfactant, but still approximately one per cent of babies develop RDS. Hyaline membranes, formed from plasma proteins which have leaked onto the lung surface through damaged capillaries and endothelial cells, line the terminal airways. Hence, RDS has also been called hyaline membrane disease, but RDS is the preferred name as the presence of hyaline membranes can only be confirmed histologically. The aim of this review is to emphasize the pathophysiology of RDS and the clinical presentation and relevance of diagnostic techniques in the current population of very prematurely born infants, highlighting the differential diagnosis. In addition, the evidence base for prophylactic and management strategies including whether new therapies and techniques of respiratory support have positively impacted on outcomes are discussed. The mortality and long term morbidity associated with very premature birth are described. Our increasing understanding that the so-called new bronchopulmonary dysplasia (BPD) and associated chronic adverse respiratory outcomes in such infants can reflect antenatal events resulting in abnormal lung growth is highlighted.

Research Article
Copyright © Cambridge University Press 2008

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1Jobe, AH. The new BPD: an arrest of lung development. Pediatr Res 1999; 46: 641–43.CrossRefGoogle ScholarPubMed
2Hamvas, A, Sessions Cole, F, Nogee, LM. Genetic disorders of surfactant proteins. Neonatology 2007; 91: 311–17.CrossRefGoogle ScholarPubMed
3Smaill, F.Intrapartum antibiotics for group B streptococcal colonization. Cochrane Database Syst Rev 2000; 2: CD000115.Google Scholar
4Sweet, D, Bevilacqua, G, Carnielli, V, Greison, G, Plavka, R, Didrik Saugstad, O et al. European consensus guidelines on the management of neonatal respiratory distress syndrome. J Perinatal Med 2007; 35: 175–86.CrossRefGoogle ScholarPubMed
5Roberts, D, Dalziel, S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Sys Rev 2006; 3: CD004454.CrossRefGoogle Scholar
6Baud, O, Foix L'Helias, L, Kaminski, M, Audibert, F, Jarreau, PH, Papiernik, F et al. Antenatal glucorticoid treatment and cystic periventricular leukomalacia in very premature infants. N Engl J Med 1999; 341: 1190–96.CrossRefGoogle Scholar
7Lee, BH, Stoll, BJ, McDonald, SA, Higgins, RDfor the National Institute of Child Health and Human Development Neonatal Research Network. Adverse neonatal outcomes associated with antenatal dexamethasone versus antenatal betamethasone. Pediatrics 2006; 117: 1503–10.CrossRefGoogle ScholarPubMed
8Stutchfield, P, Whitaker, R, Russell, Ion behalf of the Antenatal Steroids for Term Elective Caesarian Section (ASTECS) Research Team. Antenatal betamethasone and incidence of neonatal respiratory distress after elective caesarean section. Pragmatic randomised trial. Br Med J 2005; 331: 662.CrossRefGoogle Scholar
9Crowther, CA, Haslam, RR, Hiller, JE, Doyle, LW, Robinson, JSfor the Australasian Collaborative Trial of Repeat Doses of Steroids (ACTORDS) Study Group. Neonatal respiratory distress syndrome after repeat exposure to antenatal corticosteroids: a randomised controlled trial. Lancet 2006; 367: 1913–919.CrossRefGoogle Scholar
10French, NP, Hagan, R, Evans, SF, Godrfrey, M, Newnham, JP. Repeated antenatal corticosteroids: size at birth and subsequent development. Am J Obstet Gynecol 1999; 180: 114–21CrossRefGoogle ScholarPubMed
11Willet, KE, Jobe, AH, Ikegami, M, Newnham, J, Brennan, S, Sly, PD. Antenatal endotoxin and glucorticoid effects on lung morphometry in preterm lambs. Pediatr Res 2000; 48: 782–88.CrossRefGoogle ScholarPubMed
12Burri, PH. The postnatal growth of the rat lung. III. Morphology. Anat Rec 1975; 180: 7798.CrossRefGoogle Scholar
13Burri, PH. Postnatal development and growth. In: The Lung: Scientific Foundations. Crystal, RG, West, JB, Weibel, ER, Barnes, PJ (eds). Lippincott Raven, Philadelphia, USA, 1977; 1013–26.Google Scholar
14Kallapur, SG, Kramer, BW, Moss, TJ, Newnham, JP, Jobe, AH, Ikegami, M et al. Maternal glucocorticoids increase endotoxin-induced lung inflammation in preterm lambs. Am J Physiol Lung Cell Mol Physiol 2003; 284: L633–42.CrossRefGoogle ScholarPubMed
15Crowther, CA, Alfirevic, Z, Haslam, RR. Thyrotropin-releasing hormone added to corticosteroids for women at risk of preterm birth for preventing neonatal respiratory disease. Cochrane Database of Syst Rev 2004, Issue 2. Art. No.: CD000019. DOI:10.1002/14651858.CD000019.pub2.CrossRefGoogle Scholar
16Osborn, DA, Hunt, RW. Postnatal thyroid hormones for respiratory distress syndrome in preterm infants. Cochrane Database Syst Rev 2007; 1: CD005946.Google Scholar
17Eisler, G, Hjertberg, R, Lagercrantz, H. Randomised controlled trial of effect of terbutaline before elective caesarian section on postnatal respirations and glucose homeostasis. Arch Dis Child Fetal Neonatal Ed 1999; 80: F88–92.CrossRefGoogle ScholarPubMed
18Soll, RF, Morley, CJ. Prophylactic versus selective use of surfactant in preventing morbidity and mortality in preterm infants. Cochrane Database of Syst Rev 2001, Issue 2. Art. No.: CD000510. DOI:10.1002/14651858.CD000510.CrossRefGoogle Scholar
19Yost, CC, Soll, RF. Early versus delayed selective surfactant treatment for neonatal respiratory distress syndrome. Cochrane Database Syst Rev 2000; 2: CD001456.Google Scholar
20Engle, WAand the Committee on Fetus and Newborn. Surfactant replacement therapy for respiratory distress syndrome in the preterm and term neonate. Pediatrics 2008; 121: 419–32.CrossRefGoogle Scholar
21Soll, RF. Prophylactic synthetic surfactant for preventing morbidity and mortality in preterm infants. Cochrane Database Syst Rev 2000; 2: CD001079.Google Scholar
22Soll, RF. Prophylactic natural surfactant extract for preventing morbidity and mortality in preterm infants. Cochrane Database Syst Rev 2000; 2: CD000511.Google Scholar
23Soll, RF. Synthetic surfactant for respiratory distress syndrome in preterm infants. Cochrane Database Syst Rev 2000; 2: CD001149.Google Scholar
24Corbet, A, Buccciarelli, R, Goldman, S, Mammel, M, Wold, D, Long, W. Decreased mortality rate among small premature infants treated at birth with a single dose of synthetic surfactant; a multicenter controlled trial. American Exosurf Pediatric Study Group 1. J Pediatr 1991; 118: 277–84.CrossRefGoogle ScholarPubMed
25Hoekstra, RE, Jackson, JC, Myers, TF, Frantz, ID 3rd, Stern, ME, Powers, WF et al. Improved neonatal survival following multiple doses of bovine surfactant in very premature neonates at risk for respiratory distress syndrome. Pediatrics 1991; 88: 1018.Google ScholarPubMed
26Liechty, EA, Donovan, E, Purohit, D, Gilhooly, J, Feldman, B, Noguchhi, A et al. Reduction of neonatal mortality after multiple doses of bovine surfactant in low birth weight neonates with respiratory distress syndrome. Pediatrics 1991; 88: 1928.Google ScholarPubMed
27Kattwinkel, J, Bloom, BT, Delmore, P. Prophylactic administration of calf lung surfactant extract is more effective than early treatment of respiratory distress syndrome in neonates of 29 through 32 weeks' gestation. Pediatrics 1993; 92: 9098.Google Scholar
28Merritt, TA, Hallman, M, Berry, C, Pohjavuori, M, Edwards, DK 3rd, Jaaskelainen, J et al. Randomised, placebo-controlled trial of human surfactant given at birth versus rescue administration in very low birth weight infants with lung immaturity. J Pediatr 1991; 118: 581–94.CrossRefGoogle Scholar
29Halliday, HL. Recent clinical trials of surfactant treatment for neonates. Biol Neonate 2006; 89: 323–29.CrossRefGoogle ScholarPubMed
30Moya, F, Sinha, S, Gadzinowski, J, D'Agostino, R, Segal, R, Guardia, C et al. on behalf of the SELECT and STAR Study Investigators. One year follow up of very preterm infants who received lucinactant for prevention of respiratory distress syndrome: results from 2 multicenter randomised controlled trials. Pediatrics 2007; 119: e1361e1370.CrossRefGoogle Scholar
31Pfister, RH, Soll, RF, Wiswell, T. Protein containing surfactant versus animal derived surfactant extract for the prevention and treatment of respiratory distress syndrome. Cochrane Database Syst Rev 2007; 4: CD006069.CrossRefGoogle Scholar
32Stevens, TP, Blennow, M, Myers, EH, Soll, R. 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 of Syst Rev 2007, Issue 4. Art. No.: CD003063. DOI:10.1002/14651858.CD003063.pub3.CrossRefGoogle Scholar
33Soll, RF, Blanco, F. Natural surfactant extract versus synthetic surfactant for neonatal respiratory distress syndrome. Cochrane Database of Syst Rev 2001, Issue 2. Art. No.: CD000144. DOI:10.1002/14651858.CD000144.CrossRefGoogle Scholar
34Avery, ME, Tooley, WH, Keller, JB, Hurd, SS, Bryan, MH, Cotton, RB et al. Is chronic lung disease in low birthweight infants preventable? A survey of eight centres. Pediatrics 1987; 79: 2630.Google Scholar
35Morley, CJ, Davis, PG, Doyle, LW, Brion, L, Hascoet, JM, Carlin, JB. Nasal CPAP or intubation at birth for very preterm infants. N Engl J Med 2008; 358: 700708.CrossRefGoogle ScholarPubMed
36Greenough, A, Woods, S, MorleyCJ, Davis JA CJ, Davis JA. Pancuronium prevents pneumothoraces in ventilated premature infants who actively expire against positive pressure ventilation. Lancet 1984; i: 13.CrossRefGoogle Scholar
37GreenoughA, Dimitriou G, Prendergast M A, Dimitriou G, Prendergast M, Milner, AD. Synchronized mechanical ventilation for respiratory support in newborn infants. Cochrane Database Syst Rev 2008; (1): CD000456.CrossRefGoogle ScholarPubMed
38Reyes, ZC, Claure, N, Tauscher, MK, D'Ugard, C, Vanbuskirk, S, Bancalari, E. Randomised, controlled trial comparing synchronised intermittent mandatory ventilation and synchronised intermittent mandatory ventilation plus pressure support in preterm infants. Pediatrics 2006; 118: 1409–417.CrossRefGoogle Scholar
39Schulze, A, Rieger-Fackeldey, E, Gerhardt, T, Claure, N, Everett, R, Bancalari, E. Randomised crossover comparison of proportional assist ventilation and patient triggered ventilation in extremely low birthweight infants with evolving chronic lung disease. Neonatology 2007; 92: 17.CrossRefGoogle Scholar
40Herber-Jonat, S, Rieger-Fackeldey, E, Hummler, H, Schulze, A. Adaptive mechanical backup ventilation for preterm infants on respiratory assist modes – a pilot study. Intens Care Med 2006; 32: 302308.CrossRefGoogle Scholar
41McCallion, N, Davis, PG, Morley, CJ. Volume targeted versus pressure limited ventilation in the neonate. Cochrane Database Syst Rev 2005; 2: CD003666.CrossRefGoogle Scholar
42Sinha, SK, Clarke, P, Bryne, S, Donn, SM. Mechanical ventilation of very low birth weight infants: is volume or pressure a better target variable? J Pediatr 2006; 149: 308–13.Google Scholar
43Cheema, IU, Sinha, AK, Kempley, ST, Ahluwalia, JS. Impact of volume guarantee ventilation on arterial carbon dioxide tension in newborn infants: a randomized controlled trial. Early Hum Dev 2007; 83: 183–89.CrossRefGoogle Scholar
44Lista, G, Castoldi, F, Fontana, P, Reali, R, Reggiani, A, Bianchi, S et al. Lung inflammation in preterm infants with respiratory distress syndrome: effects of ventilation with different tidal volumes. Pediatr Pulmonol 2006; 41: 357–63.CrossRefGoogle ScholarPubMed
45Henderson-Smart, DJ, Bhuta, T, Cools, F, Offringa, M. Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants (Cochrane review). Cochrane Database Syst Rev 2007; 1: CD000104.CrossRefGoogle Scholar
46HIFO Study Group. Randomised study of lung frequency oscillatory ventilation in infants with severe respiratory distress syndrome. Pediatrics 1993; 122: 609–19.CrossRefGoogle Scholar
47Dimitriou, G, Greenough, A, Broomfield, D, Morton, M. Rescue high frequency oscillation, hypocarbia and neurodevelopmental outcome in preterm infants. Early Hum Dev 2002; 66: 133–41.CrossRefGoogle ScholarPubMed
48Finer, NN, Barrington, KJ. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database of Syst Rev 2006, Issue 4. Art. No.: CD000399. DOI:10.1002/14651858.CD000399.pub2.CrossRefGoogle Scholar
49Barrington, KJ, Finer, NN. Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane Database of Syst Rev 2007, Issue 3. Art. No.: CD000509. DOI:10.1002/14651858.CD000509.pub3.CrossRefGoogle Scholar
50Field, D, Elbourne, A, Truesdale, R, Grieve, R, Hardy, P, Fenton, AC et al. , on behalf of the INNOVO Trial Collaborating Group. Neonatal ventilation with inhaled nitric oxide versus ventilatory support without inhaled nitric oxide for Preterm infants with severe respiratory failure: the INNOVO multicentre randomised controlled trial (ISRCTN 17821339). Pediatrics 2005; 115: 926–36.CrossRefGoogle Scholar
51Schreiber, MD, Gin-Mestan, K, Marks, JD, Huo, D, Lee, G, Srisuparp, P. Inhaled nitric oxide in premature infants with the respiratory distress syndrome. N Engl J Med 2003; 349: 2099–107.CrossRefGoogle ScholarPubMed
52Kinsella, JP, Cutter, GR, Walsh, WF, Gerstmann, DR, Bose, CL, Hart, C et al. Early inhaled nitric oxide therapy in premature newborns with respiratory failure. N Engl J Med 2006; 355: 354–64.CrossRefGoogle ScholarPubMed
53Ballard, RA, Truog, WE, Cnaan, A, Martin, RJ, Ballard, PL, Merrill, JD et al. : NO CLD Study Group. Inhaled nitric oxide in preterm infants undergoing mechanical ventilation. N Engl J Med 2006; 355: 343–53.CrossRefGoogle Scholar
54Costeloe, Kon behalf of the EPICure Study Group. EPICure: facts and figures: why preterm labour should be treated. BJOG 2006; 113: 1012.CrossRefGoogle Scholar
55Kono, Y, Mishina, J, Takamura, T, Hara, H, Sakuma, I, Kusuda, S et al. Impact of being small for gestational age on survival and long term outcome of extremely premature infants born at 23–27 weeks gestation. J Perinat Med 2007; 35: 447–54.CrossRefGoogle Scholar
56Gonzalez, A, Sosenko, IR, Chandar, J, Hummler, H, Claure, N, Bancalari, E. Influence of infection on patent ductus arteriosus and chronic lung disease in premature infants weighing 1000 g or less. J Pediatr 1996; 128: 470–78.CrossRefGoogle ScholarPubMed
57Jobe, AH, Banaclari, E. NICHD/NHLSI/ORD Workshop Summary. Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001; 163: 1723–29.CrossRefGoogle Scholar
58Johnson, AH, Peacock, JL, Greenough, A, Marlow, N, Limb, ES, Marston, L et al. for the United Kingdom Oscillation Study Group. High frequency oscillatory ventilaton for the prevention of chronic lung disease of prematurity. New Engl J Med 2002; 347: 633–42.CrossRefGoogle Scholar
59Watterberg, KL, Demers, LM, Scott, SM, Murphy, S. Chorioamnionitis and early lung inflammation in infants in whom bronchopulmonary dysplasia develops. Pediatrics 1996; 97: 210–15.Google ScholarPubMed
60Van Marter, LJ, Ammann, O, Allred, EN, Leviton, A, Pagano, M, Moore, M et al. Chorioamnionitis, mechanical ventilation and postnatal sepsis as modulators of chronic lung disease in preterm infants. J Pediatr 2002; 140: 171–76.CrossRefGoogle ScholarPubMed
61Husain, AN, Siddiqui, NH, Stocker, JT. Pathology of arrested acinar development in postsurfactant bronchopulmonary dysplasia. Hum Pathol 1998; 29: 710–17.CrossRefGoogle ScholarPubMed
62Greenough, A, Alexander, J, Burgess, S, Chetcuti, PA, Cox, S, Lenney, W et al. Home oxygen status on rehospitalisation and primary care requirements of chronic lung disease infants. Arch Dis Child 2002; 86: 4043.CrossRefGoogle Scholar
63Greenough, A, Alexander, J, Burgess, S, Chetcuti, P, CoxS, Lenny W S, Lenny W et al. Health care utilisation of chronic lung disease infants related to hospitalisation for RSV infection. Arch Dis Child 2001; 85: 463–68.CrossRefGoogle ScholarPubMed
64Vrijlandt, EJ, Gerritsen, J, Marike Boezen, H, Duiverman, EJand the Dutch POPS-19 Collaborative Study Group. Gender differences in respiratory symptoms in 19 year old adults born preterm. Respir Res 2005; 6: 117.CrossRefGoogle Scholar
65Filippone, M, Sartor, M, Zachello, F, Baraldi, E. Flow limitation in infants with bronchopulmonary dysplasia and respiratory function at school age. Lancet 2003; 361: 753–54.CrossRefGoogle ScholarPubMed
66Wood, NS, Costeloe, K, Gibson, AT, Hennessy, EM, Marlow, N, Wilkinson, ARfor the EPICure Study Group. The EPICure study: associations and antecedentst of neurological and developmental disability at 30 months of age following extremely preterm birth. Arch Dis Child Fetal Neonatal Ed 2005; 90: F134F140.CrossRefGoogle Scholar
67Marlow, N, Wolke, D, Bracelwell, MA, Samara, Mfor the Epicure Study Group. Neurologic and developmenteal disability at six years of age after extremely preterm birth. N Engl J Med 2005; 352: 919.CrossRefGoogle Scholar