Clinical trial evidence for the effectiveness of corticosteroids in the prevention of CLD is strong and the use of this treatment in the clinical setting has become popular. Follow up studies have started to appear in the literature and have suggested that there may be a danger in this practice 1-6. This clinical practice guideline attempts to provide some guidance to the practicing Paediatrician on the interpretation of this evidence in the clinical setting.
The term bronchopulmonary dysplasia (BPD) was first used by Northway in 1967 to describe a condition characterized by chronic respiratory failure in neonates treated with mechanical ventilation for a primary lung disease.7 Today most neonates with chronic respiratory failure are preterms with a history of treatment by mechanical ventilation for respiratory distress syndrome. The disease tends to be less severe and does not follow the clinical and X-ray phases described by Northway.
There is no diagnostic marker for the condition so although the onset of the condition is known to occur very early in postnatal life, the diagnosis is made in infants who remain oxygen dependent and in whom other conditions have been excluded. BPD is commonly defined as oxygen dependency at 28 days of age.8-10 Some definitions also include X-ray evidence of BPD or a history of mechanical ventilation in the first week of life.11-17 One of the weaknesses of this definition is that it is very common for very preterm infants below 28 weeks gestation to require oxygen for more than 28 days and most of these are normal. Chronic lung disease (CLD) generally refers to infants below 32 weeks who remain oxygen dependent at 36 weeks postmenstrual age. This definition has been found to be a more accurate predictor of long term outcome.18 In the clinical setting the terms are often used interchangeably. This guideline uses the term CLD and refers to either definition above: that is oxygen dependency at 28 days of life or at 36 weeks postmenstrual age. However defined, chronic lung disease is an important problem. Severe cases have pulmonary hypertension and progress to cor pulmonale which is usually fatal. The treatment of CLD is costly. Most infants require a prolonged hospital stay and some continue with home oxygen therapy after discharge. Infants with CLD require more frequent hospital admission and have a higher risk of dying during the first year of life. Poor growth and abnormal neurological development are additional problems that these infants may face.
The incidence of CLD depends on the definition. In the Malaysian Paediatric Association Very Low Birth Weight (VLBW) study, 4% of 962 VLBW infants born in 20 Malaysian hospitals were oxygen dependant at 28 days and had X-ray evidence of BPD while 28% died and 68% were normal.19 In developed countries where the mortality is lower BPD has reported in 11 to 57% of survivors.9,11-17,20,21 Survival of VLBW infants is rapidly improving in Malaysia and it is reasonable to assume that CLD will become more common.19
Inflammation plays an important role in the pathogenesis of CLD. This progresses to lung destruction and abnormal repair. Corticosteroids have been found to reduce the inflammatory response and decrease airways resistance.
There have been more than 35 randomised controlled trials testing corticosteroids, mainly dexamethasone in the prevention of CLD.22 They have used courses of therapy ranging from 3 to 42 days. A 12 - 14 day course seems to be the most common.22-24 Early post natal steroids refers to corticosteroids begun within the first 96 hours after birth; moderately early, 7-14 days after birth; and delayed 3 or more weeks after birth.22-24
Corticosteroids have also been used in neonates for the prevention and treatment of post-extubation stridor and extubation failure and may have some benefit.25
Early Postnatal Corticosteroids (<96 hours)
A Cochrane systematic review of 19 trials involving almost 2500 patients given early postnatal steroids or placebo found the following:
Reduced oxygen dependency at 28 days and 36 weeks postmenstrual age, reduced overall incidence of death or chronic lung disease, reduced failure to extubate and reduced need for later steroids, reduced pulmonary air leak and patent ductus arteriosus.22 They did not show a reduction in overall mortality.
There was an increased risk of hyperglycaemia, hypertension, and hypertrophic cardiomyopathy, increased growth failure, increase gastro-intestinal bleeding and intestinal perforation. There was no evidence of increased IVH, PVL, ROP, NEC, pulmonary haemorrhage, or infection.
Long Term Outcome
The reviewers were able to locate two follow up studies.1,6 Important long term complications were found and these included: increased risk of abnormal neurological examination, increased cerebral palsy and developmental delay, and increased death or developmental delay.
The reviewers of the review recommend further follow up studies but in the mean time conclude that the benefits of early postnatal steroids may not outweigh the risks. Early postnatal steroids are precluded as the treatment should only be considered in infants who cannot be weaned from mechanical ventilation. A further multicentre study is underway.
Moderately Early Postnatal Corticosteroids (7-14 days)
A Cochrane systematic review of 7 trials involving almost 600 patients found the following:
There was reduced mortality at 28 days, reduced CLD at both 28 days and 36 weeks postmenstrual age, reduced aggregated death or CLD at 36 weeks, reduced failure to extubate.23
The following complications were found: increased hyperglycaemia, hypertension, and hypertrophic cardiomyopathy, increased gastrointestinal bleeding, and increased infection rate. There was no increase in IVH, NEC, and ROP.
Long Term Outcome
The reviewers found only one long term study on 36 infants followed up for 15 months.26 This was unable to show any increase in abnormal neurological examination and combined death or abnormal neurological examination.
The reviewers concluded that there were both benefits and adverse effects and that there was no reliable evidence concerning the long term effects of postnatal corticosteroids. Clinicians must weigh up each individual case.
Delayed Postnatal Corticosteroids (> 3 weeks)
There are 9 trials involving over 550 subjects.
A Cochrane systematic review found that there was reduced failure to extubate, need for further late steroids, and need for home oxygen.24 Mortality was not affected but there was a decrease in aggregated mortality and CLD.
Hypertension was increased but hyperglycaemia was not. Gastrointestinal complications and infection were not increased.
Long Term Outcome
Long term follow up was reported in one study.4,5 This showed an increase in abnormal neurological examination both overall and in survivors. There was no significant increase in cerebral palsy or death and cerebral palsy.
The authors concluded that the use of delayed steroids should be reserved for ventilator dependant infants in whom it is felt that steroids are essential to facilitate extubation.
In summary postnatal steroids do show benefits in weaning from mechanical ventilation and reducing CLD and possibly also mortality. However the adverse effects are considerable and these include abnormal neurological findings and cerebral palsy on follow up. Adverse effects may outweigh the benefits.
Recommendations (with Grading according to strength of evidence)*
The benefits and risks of postnatal corticosteroid use in oxygen dependant preterm infants should be weighed up in each individual case. (Grade A)
Postnatal corticosteroids should be reserved for situations where there is evidence of chronic lung disease such as failure of the X-ray to clear and continued high ventilator settings after 7 days and it is apparent that weaning may not be possible without steroids. (Grade A)
Postnatal corticosteroids for the purpose of preventing or treating CLD should not be given to infants below 7 days of age. (Grade A)
A suggested regime would be a starting dose of 0.5mg/kg/day tapering after 3 days, keeping the duration of treatment to a minimum (Grade A).
These recommendations should be revised when data becomes available from ongoing trials (DART Study, Doyle 2000) (Grade A)
Each Paediatric department should develop its own written policy on the indications of postnatal steroids.
Antenatal corticosteroids remain proven and beneficial in reducing RDS and their use should not be influenced by these new recommendations on the use of postnatal steroids (Grade A).
*Grading of Recommendations based on AHCPR 1994.
Yeh TF, Lin YJ, Huang CC et al. Early dexamethasone therapy in preterm infants: a follow-up study. Pediatrics 1998;101:E7.
Doyle LW, Davis PG. Postnatal corticosteroids in preterm infants - effects on mortality and cerebral palsy. Pediatr Res 1999;45:194A.
Jones R, Wincott E, Elbourne D, Grant A. Controlled trial of dexamethasone in neonatal chronic lung disease: a 3 year follow-up. Pediatrics 1995;96:897-906.
Goldstein DJ, Waldrep EL, VanPelt JC, O'Shea TM. Developmental outcome at 5 years following dexamethasone use for very low birth weight infants. Pediatr Res 2000;47:310A (Abstract 1832).
O'Shea TM, Kothadia JM, Klinepeter KL, Goldstein DJ, Jackson BG, Weaver RG, Dillard RG. Randomized placebo-controlled trial of a 4-day tapering course of dexamethasone to reduce the duration of ventilator dependency in very low birth weight infants: outcome of study participants at 1-year adjusted age. Pediatrics 1999;104:15-21
Sinkin RA, Dweck HS, Horgan MJ, Callaher KJ, Cox C, Maniscalco et al. Early dexamethasone - Attempting to prevent chronic lung disease. Pediatrics 2000;105:542-48.
Northway WH Jr, Rosan RC, Porter DY. Pulmonary disease following respirator therapy of hyaline-membrane disease. N Engl J Med 1967;276:357.
Avery ME, Tooley WH, Keller JB. Is chronic lung disease in low birth weight infants preventable? A survey of eight centres. Pediatrics 1987;79:26-30.
Donoghue D, Cust A. Report of the Australian and New Zealand Neonatal Network 1999.
Sinkin RA, Cox C, Phelps DL. Predicting risk of bronchopulmonary dysplasia: selection criteria for clinical trials. Pediatrics 1990;86:728-36.
Singer L, Yamashita T, Lilien L, Collin M, Baley J. A Longitudinal Study of Developmental Outcome of Infants With Bronchopulmonary Dysplasia and Very Low Birth Weight. Pediatrics 1997;100:987-93.
Merritt TA, Hallman M, Berry C, Pohjavouri M, Edwards DK 3rd, Jaaskelainen J et al. Randomised controlled trial of human surfactant given at birth versus rescue administration in very low birth weight infants with lung immaturity, J Pediatr 1991;119:581-94.
Soll RF, Hoekstra RE, Fangman JJ, Corbet AJ, Adama JM, James LS, et al. Multicentre trail of single-dose modified bovine surfactant extract (Survanta) for prevention of respiratory distress syndrome. Pediatrics 1990;85:1092-1102.
Bose C, Corbet A Bose G, Gaarcia-Prats J, Combardy L, Wold D, et al. Improved outcome at 28 days of age for very low birth weight infants treated with a single dose of synthetic surfactant. J Pediatr 1990;117:947-53.
Liechty EA, Donovan E, Purohit D, Gilhooly J, Fieldman B, Noguchi A, et al. Reduction of neonatal mortality after multiple doses of bovine surfactant in low birth weight neonates with respiratory distress syndrome. Pediatrics 1991;88:19-28.
Long WA, Thompson T, Sundell H, Schumacher R, Volberg F, Guthrie R. Effects of two rescue doses of a synthetic surfactant on mortality rate and survival without bronchopulmonary dysplasia in 700 to 1350 gram infants with respiratory distress syndrome. The American Exosurf Study Group I. J Pediatr 1991;118:595-605.
Hoekstra RE, Jackson JC, Myers TF, Frantz ID, 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;88:10-18.
Shennan AT, Dunn MS, Ohlsson A, Lennox K, Hoskins EM. Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period. Pediatrics 1988;82:527-32.
Malaysian VLBW Study Group. Report of the Malaysian Paediatric Association Very Low Birth Weight Study 1996. MPA 1998.
Lemons JA, Bauer CR, Oh W, Korones SB, Papile LA, Stoll BJ et al. Very low birth weight outcomes of the National Institutes of Child Health and Development Neonatal Research Network, January 1996 through December 1996. Pediatrics 2001;107:e1.
Fenton AC, Mason e, Clarke M, Field DJ. Chronic lung disease following neonatal ventilation. Changing incidence in a geographically defined population. Pediatr Pulmonol 1996;21:24-7.
Halliday HL, Ehrenkranz RA. Early postnatal (<96 hours) corticosteroids for preventing chronic lung disease in preterm infants (Cochrane Review). In: The Cochrane Library, Issue 2, 2001. Oxford: Update Software.
Halliday HL, Ehrenkranz RA. Moderately early (7-14 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants (Cochrane Review). In: The Cochrane Library, Issue 2, 2001. Oxford: Update Software.
Halliday HL, Ehrenkranz RA. Delayed (>3 weeks) postnatal corticosteroids for chronic lung disease in preterm infants (Cochrane Review). In: The Cochrane Library, Issue 2, 2001. Oxford: Update Software.
Markovitz BP, Randolph AG. Corticosteroids for the prevention and treatment of post-extubation stridor in neonates, children and adults (Cochrane Review). In: The Cochrane Library, Issue 2, 2001. Oxford: Update Software.
Cummings JJ, D'Eugenio DB, Gross SJ. A controlled trial of dexamethasone in preterm infants at high risk for bronchopulmonary dysplasia. N Engl J Med 1989;320:1505-10.
This Guideline was formulated by and represents the views of the following people*:
Perak College of Medicine
Representatives of Perinatal Society of Malaysia
Lim Nyok Ling
Hospital Sultanah Aminah
International Medical University
Yong Sin Chuen
Lecturer in Paediatrics
National University of Malaysia
Representatives of the College of Paediatrics
Chye Joon Kin
Sunway Medical Centre
Lim Wei Ling
Sunway Medical Centre
Representative of Malaysian Paediatric Association
Irene GS Cheah
Hospital Kuala Lumpur
Prof Boo Nem Yum
Professor of Neonatology
National University of Malaysia
Professor in Neonatology
University of Malaya Medical Centre
Dr S Gunasegaran
Damansara Specialist Hospital
*Addresses correct at time of formulation of guideline
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