Microsoft word - cnld - 2012.doc

North Trent Neonatal Network Clinical Guideline

Title: Chronic Neonatal Lung Disease- Management of
Author: Aiwyne Foo
Date written: 10 November 2011
Date ratified: September 2012
Review date: September 2015

This clinical guideline has been developed to ensure appropriate
evidence based standards of care throughout the North Trent Neonatal
Network. The appropriate use and interpretation of this guideline in
providing clinical care remains the responsibility of the individual
clinician. If there is any doubt discuss with a senior colleague.

Best practice recommendations represent widely used evidence-based
practice and high quality standards that all Neonatal Units across the
Network should implement. Subsequent suggested recommendations
may be put into practice in local units. However, alternative appropriate
local guidelines may also exist.


A. Summary page
• To provide, as far as possible, an evidence based approach to the management
of evolving chronic neonatal lung disease. • The terms chronic lung disease (CLD) and bronchopulmonary dysplasia (BPD) are both used in this guideline according to where the evidence originated from. • Where prevention is not possible, to treat or minimize the risk factors contributing to the development and worsening of CLD: o Respiratory distress syndrome o Positive pressure ventilation o Supplemental oxygen use o Patent ductus arteriosus o Infection o Growth failure
Therapeutic options are as follow:
1. Commence caffeine early on. (B)
2. Postnatal corticosteroids:
In general, use will be in tertiarty neonatal unit, to promote extubation, and to reduce mortality and CLD. Use dexamethasone as choice of steroid as limited evidence of other forms of steroids. Avoid use in 1st 2 weeks of life. (A) Identify and treat other causes for continued ventilator dependence before use Cautious use in extreme preterm infants > 2 w of life with high requirement of mechanical ventilation, and those re-ventilated who remain ventilator-dependent for a significant length of time. (A) consider discussion with tertiary neonatologist/respiratory specialist before use. Discuss risks and benefits with parents. (D) (refer to appendix 2) Consider the DART or the Mini-dex regime (see below 4.1.3.5) Consider a repeat course with a prolonged wean for infants who initially responded to therapy but relapsed or deteriorated on withdrawal. (D) Discussion with respiratory specialist/ tertiary neonatologist the use of steroids, in infants >36 w PMA with CLD who are still nCPAP or high flow oxygen dependent to lessen detrimental effects on neuro-development and facilitate discharge home. (D) 3. Consider a short term trial of diuretics – thiazide and spironolactone, and possibly a longer course if necessary. (A) o Infants >36 w PMA with CLD requiring oxygen therapy should have their oxygen saturation kept ≥ 93%, and to avoid <90% as far as possible. o Refer to Long Term Oxygen Therapy in Children Guideline for:
B. Full guideline

1.0 Background

Chronic neonatal lung disease (CNLD/CLD) or bronchopulmonary dysplasia
(BPD) is common in very preterm infants with respiratory distress syndrome
(RDS). Histologically, CLD is characterised by impaired alveolarisation and
abnormal pulmonary vasculogenesis following inadequate tissue growth and
repair.1
Major risk factors include preterm birth per se, supplemental oxygen and
positive pressure ventilation, patent ductus arteriosus, and infection.
These factors trigger a systemic and pulmonary inflammatory response. CLD
is associated with increased mortality, poor neurodevelopmental outcome,
significant long term cardiorespiratory sequelae including pulmonary
hypertension, decreased lung volume in the neonatal period, poor airway
function and limited exercise tolerance in later childhood.
CLD is defined as a requirement for supplemental oxygen for 21 of the 1st 28
days of life, and identifies 3 grades of severity (mild, moderate or severe)
depending on the level of supplemental oxygen and mechanical ventilatory
support at 36 weeks post menstrual age (PMA).1,2
2.0 Aim

To provide, as far as possible, an evidence-based guide to the management
of evolving CLD, with emphasis on a multimodal approach- including
adequate nutrition, careful fluid management, effective and safe
pharmacotherapy, and respiratory support aiming at minimal lung injury.
3.0 Areas outside remit
Early post-natal steroids use
Details of home oxygen and long term oxygen therapy
4.0 Core guideline
4.1 Pharmacological Treatment

4.1.1 Caffeine
4.1.1.1 Reduces the risk of CLD and improves the primary outcome of survival without neurodevelopmental impairment at 18 to 21 months corrected age.3 Recommendation: Commence caffeine early on – before extubation and for all infants <30 weeks gestation. 4.1.2.1 Given for 4 weeks, when compared to placebo, reduced the risk of death and BPD at 36 weeks PMA in extremely low birth weight infants (<1000g).4 4.1.2.2 Given intramuscularly, did not increase mortality or neurodevelopmental impairment at 18 to 22 months corrected age. 4.1.2.3 Long term risk benefit ratio for neurodevelopment uncertain. Recommendation: At present not considered for regional use. 4.1.3 Postnatal corticosteroids 4.1.3.1 Early (<8 days) systemic use to prevent CLD: 28 RCTs with 3740 infants where meta-analyses showed a decreased risk of death and BPD at 28 d and 36 w PMA, PDA and ROP, GI bleeding and intestinal perforation were adverse effects, alongside increased risk of hyperglycaemia, hypertension, hypertrophic cardiomyopathy and growth failure. Late outcomes were reported in 12 trials- severe adverse neurological effects (developmental delay, cerebral palsy and abnormal neurological examination) were found at follow-up.7 4.1.3.2 Delayed (>7 d) systemic use facilitated extubation, reduced the risk of BPD and death or BPD at both 28 d and 36 w PMA. Short term adverse effects include hyperglycaemia and hypertension and a trend towards an increased risk of infection and GI bleeding. There was no effect on the combined rate of death or cerebral palsy at follow-up. 4.1.3.3 Moderately early (7-14 d) systemic use showed similar results to delayed systemic use with limited data on long term outcome.9 4.1.3.4 Inhaled corticosteroids: reviews to date revealed no significant benefits of its use to prevent CLD, nor there is evidence that it confers benefit over systemic corticosteroids in ventilator dependent infants.38 4.1.3.5 Low dose dexamethasone after 1st week of life facilitates extubation and shortens duration of ventilation in very preterm/extremely low birth weight infants without any obvious short term complications. (DART) - Doses used were 0.15mg/kg for 3 days, followed by 0.10mg/kg for 3 days, then 0.05mg/kg for 2 days and 0.02mg/kg for 2 days.11 At 2 year follow-up, although sample size was small and unable to provide definitive evidence on long term effects, low dose dexamethasone was not associated with long term morbidity.12 A small non-randomised controlled trial showed that low dose dexamethasone 0.05mg/kg/day for 10 days followed by alternated day-doses for 6 days facilitated extubation without significant short term side effects. A 5-year observational study also reported similar results with very low dose dexamethasone – starting at 0.05mg/kg/day, reducing over 9 days with a cumulative dose of 24mg/kg.32 4.1.3.6 higher cumulative dexamethasone doses administered after the 1st week of life may decrease the risk for BPD without the risk of increasing the risk for neuro-developmental sequelae in ventilated preterm infants.13 • Use dexamethasone as choice of steroid as limited evidence with other • Avoid use in 1st 2 weeks of life • Identify and treat other causes for continued ventilator dependence • Cautious use in extreme preterm infants > 2 w of life with high requirement of mechanical ventilation, and those re-ventilated for whatever reason and remain ventilator-dependent for a significant length of time. • Discuss with parents risks and benefits of steroids. (refer to parental • Consider a repeat course with or without a prolonged wean for infants who initially responded to therapy but relapsed or deteriorated on withdrawal. • Discussion with respiratory specialist/tertiary neonatologist the use of steroids, in infants >36 w PMA with CLD who are still nCPAP or high flow oxygen dependent to lessen detrimental effects on neuro-development and facilitate discharge home. 4.1.4.1 In preterm infants >3 weeks of age with CLD, a 4 week treatment with thiazide and spironolactone improved lung compliance and reduced the need for frusemide. A single study showed this combination decreased the risk of death.14 4.1.4.2 In preterm infants <3 weeks of age developing CLD, frusemide has either inconsistent effects or no detectable effect. In infants >3 weeks of age with CLD, frusemide improves lung compliance and oxygenation. However, there is lack of data on important clinical outcomes.15 • A short term trial (2-4 weeks) of diuretics eg combined thiazide and spironolactone may be used in preterms with evolving or established CLD. • A longer course many be needed in some infants. • Side effects eg hyponatraemia must be monitored and treated. 4.1.5.1 Systematic reviews of short term studies demonstrated increased respiratory compliance and reduced resistance after bronchodilator therapy in infants with BPD.16 4.1.5.2 Inhaled salbutamol has no clinical benefits in intubated preterm infants with evolving BPD.17 • Insufficient evidence to support the routine use of bronchodilators in 4.1.6.1 in animal models of persistent pulmonary hypertension of the newborn, inhaled nitric oxide improves gas exchange and lung structural development.18 4.1.6.2 however, in infants with evolving BPD ventilated between 7 and 21 d of life, long term administration of iNO did not decrease rate of death or BPD at 36 w PMA.19 4.1.6.3 early use of nitric oxide in very preterm infants did not improve survival without BPD or brain injury in a large RCT involving 800 infants.20 • Routine use of this treatment modality is not justified.
4.2 Oxygen administration
4.2.1 Treating hypoxia whilst limiting oxygen toxicity is the goal.21-22 4.2.2 the BOOST and STOP-ROP RCTs assessed oxygen saturations targets in preterm infants after 28 d: the former found the high saturation group received oxygen for longer but no difference in primary outcome at 1 year corrected, the latter found a trend towards a beneficial effect of a higher oxygen saturation target.23,24 4.2.3 BOOST II trial stopped recruitment when a safety analysis in Dec 2010 showed an increased survival at 36 w PMA in the higher oxygen target group 91-95% saturation compared to lower 85-89% saturation (mortality 17.3% vs 14.4%)25 4.2.4 the SUPPORT trial showed that a lower target range of oxygenation (85-89%) as compared to a higher one (91-95%), did not significantly decrease the composite outcome of severe retinopathy or death, but resulted in an increase in mortality and a substantial decrease in severe retinopathy among survivors.33 • Target oxygen saturation for <36 w PMA between 91-95%.
4.3 Patent Ductus Arteriosus and Fluid Management
4.3.1 presence of a PDA and a high fluid intake are associated with an increase risk of BPD likely due to pulmonary fluid overload.26 4.3.2 prophylactic indomethacin and ibuprofen are equally effective in closing PDA but do not prevent BPD.27 • Avoid excessive fluid intake in the presence of a significant PDA. • Refer to NTNN guideline on Management of the Patent Ductus
4.4 Nutrition
4.4.1 BPD is associated with a low lean mass and low functional residual capacity is associated with intrauterine growth restriction and duration of supplemental oxygen.28 • Optimum nutrition from as early on as possible. • Consider use of high energy formula in reduced quantities to avoid fluid overload and gastroesophageal reflux, whilst maintaining and promoting growth eg SMA High Energy 130ml/lg/day or Infatrini 120ml/kg/day has the same calories as 150ml/kg/day of preterm formulae.
4.5 Respiratory Support Strategies and Surfactant

Refer to NTNN Ventilation and RDS guidelines
4.6 Long term oxygen therapy

4.6.1 Hypoxaemia causes pulmonary hypertension, a complication of CLD with up to 30% mortality. Low oxygen saturations are also associated with poor growth and poor sleep quality.29 4.6.2 Oxygen titration should be done using pulse oximetry including periods of different activities. 4.6.3 Weaning of supplemental oxygen should only be done based on satisfactory recordings during a trial of lower flow. 4.6.4 There is insufficient evidence to say weaning for increasing hours a day or step-wise weaning to a continuous lower flow is a better method.29 4.6.5 Discharge planning and management of home oxygen in infants with CLD is extensively covered in Long Term Oxygen Therapy in Children Guideline. Infants >36 w PMA with CLD requiring oxygen therapy should have their oxygen saturation kept ≥ 93%, and to avoid <90% as far as possible. • Refer to Long Term Oxygen Therapy in Children Guideline. 6) Audit criteria

• Routine use of caffeine in preterms <1250g
• Avoid use of dexamethasone <2 w of life
• At 36 w PMA - maintenance of oxygen saturations > 93%

7) References

1. Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care
Med 2001;163:1723-9
2. Schulzke SM, Pillow J. The management of evolving bronchopulmonary
dysplasia. Paediatric Respir Rev 2010;11:143-8
3. Schmidt B, Robert RS et al. Long term effects of caffeine therapy for apnea
of prematurity. N Engl J Med 2007;357:1893-902
4. Tyson JE, Wright LL et al. Vitamin A supplementation for extremely low
birth weight infants, National Institute of Child health and Human development
Neonatal research network. N Engl J Med 1999;340:1962-8
5. Ambalavanan N, Tyson JE et al. Vitamin A supplementation for extremely
low birth weight infants: outcome at 18-22 months. Pediatrics 2005;115:e249-
6. Schmidt B, Roberts R et al. Evidence-based neonatal drug therapy for
prevention of bronchopulmonary dysplasia in very low birth weight infants.
Neonatology 2008;93:284-7
7. Halliday HL, Ehrenkranz RA, Doyle LW. Early (<8 days) postnatal
corticosteroids for preventing chronic lung disease in preterm infants.
Cochrane database Syst Rev 2010;CD001146
8. Halliday HL, Ehrenkranz RA, Doyle LW. Late (>7 days) postnatal
corticosteroids for chronic lung disease in preterm infants. Cochrane database
Syst Rev 2009; CD001145
9. Halliday HL, Ehrenkranz RA, Doyle LW. Moderately early (7-14 days)
postnatal corticisteroids for preventing chronic lung disease in preterm infants.
Cochrane Database Syst Rev 2011;CD001144
10. (a) Shah VS, Ohlsson et al. early administration of inhaled corticosteroids
for preventing chronic lung disease in ventilated very low birth weight preterm
neonates. Cochrane Database Syst Rev 2007;CD001969
10. (b) Shah SS, Ohlsson A, Halliday H et al. Inhaled versus systemic
corticosteroids for the treatment of chronic lung disease in ventilated very low
birth weight preterm infants. Cochrane Database of Syst Rev 2007,CD002057
11. Doyle LW, Davis PG, Morley C et al. Low dose dexamethasone facilitated
extubation among chronically ventilator-dependent infants: A Multicenter,
International, Randomised, Controlled trial. Pediatrics 2006; 117:75-83
12. Doyle LW Davis PG et al. Outcome at 2 years of age Infants from the
DART 1 study. Pediatrics 2007;119:716-21
13. Onland W, Offringa M et al. Finding the optimal postnatal dexamethasone
regimen for preterm infants at risk of bronchopulmonary dysplasia: A systemic
review of placebo controlled trials. Pediatrics 2009;123:367-77
14. Stewart A, Brion LP, Ambrosio-Perez I. Diuretics acting on the distal
tubules fro preterm infants with (or developing) chronic lung disease.
Cochrane database syst Rev 2010; CD001817
15. Stewart A, Brion LP. Intravenous or enteral loop diuretics for preterm infants with (or developing) chronic lung disease. Cochrane database syst Rev 2011; CD001453 16. Ng GY, da S, Ohlsson A. bronchodilators for the prevention and treatment of chronic lung disease in preterm infants. Cochrane database syst rev 2009; CD003214 17. Denjean A, Paris-Llado J et al. Inhaled salbutamol and beclmethasone for preventing bronchopulmonary dysplasia: a randomized double-blind study. Eur J Pediatr 1998;157:926-31 18. Abman SH. Recent advances in the pathogenensis and treatment of persistent pulmonary hypertension of the newborn. Neonatology 2007;91:283-90 19. Barrington KJ, Finer NN. Inhaled nitric oxide for preterm infants: a systemic review. Pediatrics 2007;120:1088-99 20. Mercier JC, Hummler H et al. inhaled nitric oxide for prevention of bronchopulmonary dysplasia in premature babies (EUNO): a randomized controlled trial. Lancet 2010;376:346-54 21. Saugstad OD. Oxygen and retinopathy of prematurity. J Perinatol 2006;26(suppl 1):S46-50 22. Tin W, Gupta S. optimum oxygen therapy in preterm babies. ADC fetal and neonatal ed 2007;92:F143-7 23. Askie LM, Henderson-Smart DJ et al. Oxygen saturation targets and outcomes in extremely preterm infants. N Engl J Med 2003;349:959-67 24. Supplemental therapeutic oxygen for prethreshold retinopathy pf prematurity (STOP-ROP), a randomized controlled trial. I: primary outcomes. Pediatics 2000;105:295-310 25. Stenson B et al for BOOST II UK. Increase 36-week survival with high oxygen saturation target in extreme premature infants. N Engl J Med 2011;364:1680-2 26. Oh W, Poindexter BB et al. Association between fluid intake and weight loss during the first 10 days of life and risk of bronchopulmonary dysplasia in extremely low birth weight infants. J Pediatr 2005;147:786-90 27. Ohlsson A, Walia R et al. Ibuprofen for the treatment of patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane database syst rev 2008;CD003481 28. Hulskamp G, Lum S et al. Association of prematurity, lung disease and body size with lung volume and ventilation inhomogeneity in unsedated neonates: a multicentre study. Thorax 2009;64:240-5 29. Primhak RA. Oxygen titration strategies in chronic neonatal lung disease. Paediatric Respr Rev 2010;11:154-7 30. British thoraciv Society Home Oxygen Guideline Group (Paediatric Section). Long Term Oxygen therapy in Children. Thorax 2009;64:suppl II. 31. Yates HL, Newell SJ. Mini-dex: Very low dose dexamethasone (0.05mg/kg/day) in chronic lung disease. ADC 2011;96(3):F190-4 32. Tanney K et al. Extremely low dose dexamethasone to facilitate extubation in mechanically ventilated preterm babies. Neonatology 2011;100(3):285-9 33. SUPPORT study group of the Eunice Kennedy Shriver NICHD Neonatal Research Network. N Engl J Med 2010;362:1959-69
C. Appendices
1) Evidence grading
2) others relevant to guideline
Appendix 1 Grades of recommendation

Grade
Requires at least one meta analysis, systematic review or RCT rated as 1++, and directly applicable to the target population, and demonstrating overall consistency of results Requires a body of evidence including studies rated as 2++, directly applicable to the target population, and demonstrating overall consistency of results; or Extrapolated evidence from studies rated as 1++ or 1+ Requires a body of evidence including studies rated as 2+, directly applicable to the target population and demonstrating overall consistency of results; or extrapolated evidence from studies rated as 2++ Evidence level 3 or 4; or Extrapolated evidence from studies rated as 2+
Appendix 2
Background
Chronic lung disease of prematurity occurs in some babies who have been
born early. It is likely to happen if the baby has been born prematurely (less
than 30 weeks gestation) and has+ required ventilation following birth.
The lungs of premature babies lack a chemical called surfactant. Chronic
lung disease usually develops gradually due to the effects of ventilation and
also infection which lead to damage to these lungs.
Sometimes chronic lung disease is severe enough to make it difficult for a
baby to come off the breathing machine or in extreme circumstances the baby
may die.
Dexamethasone is a steroid medicine which reduces chronic lung disease
and improves the baby’s breathing and as a result in most cases the baby is
able to come off the ventilator1 and in lower amounts of oxygen.
Why is Dexamethasone treatment suggested for my baby?
Your baby requires a significant amount of breathing support and a high
oxygen level and is amongst those babies who are at risk of severe chronic
lung disease. To help your baby come off the ventilator it is felt that they
would benefit from treatment with Dexamethasone.
What are the advantages of Dexamethasone treatment for my baby?
In most cases, the use of Dexamethasone will help your baby come off the
ventilator, although your baby may well still need some support in oxygen
given though the nose or by a special machine call a CPAP machine
(Continuous Positive Airway Pressure). It is hoped that once your baby is off
the ventilator, the lungs can begin that long process of repair and healing.
What are the disadvantages for my baby?
Dexamethasone is a powerful medication which can cause other problems on
its own. Some of these are listed below:-
Bleeding in the stomach. We treat this by using another medication that
reduces the production or effect of acid on the stomach walls.
It can also cause a temporary increase in blood sugar and the baby’s blood
pressure. These would be monitored regularly and if necessary treated or the
medication stopped altogether2.
There is a small chance of an increased risk of infection. If there is any
suspicion of infection, we would be sending some blood samples to the
laboratory and then starting your baby on antibiotics.
Poor weight gain and head growth. Because of this we would also be
monitoring your baby’s weight and head circumference regularly.
While some studies have suggested that there may be an increased risk of
cerebral palsy3 (movement difficulties associated with some degree of brain
damage), other studies have suggested that there is no increased risk.4.5.6.7.8
It is however important that you know about this. If a baby is extremely
premature and requires long periods on the breathing machine then they also
do have an increased risk of having cerebral palsy. In these situations, we do
need to weigh the risks of continued stay on the breathing machine with those
of giving your baby Dexamethasone.
What if my baby does not receive the treatment?
If your baby does not receive treatment with Dexamethasone, it may well be
that your baby will either require a longer period on the breathing machine or
may die as they will not be able to come off the ventilator.
What dose the course of treatment consist of?
The course of treatment in our unit currently consists of twice daily doses of
Dexamethasone starting with an initial dose treatment for 3 days, followed by
reduced intermediate dose treatment for another 3 days and then low dose
treatment for 3 days and the treatment is then stopped. This means your
baby would have this treatment for 9 days in total. Usually only one course of
treatment is given, but very occasionally it may be necessary to give a second
course of treatment or continue on a low dose treatment on alternate days in
severe cases of chronic lung disease.
How quickly does the treatment work?
Usually by the second to third day of starting treatment we would normally see
a response to the steroid treatment and most babies would be able to come
off the ventilator during the treatment’s first week.
There is still a chance that your baby may need to be put back on the
ventilator after successfully coming off but any period of time your baby
spends off the ventilator would also contribute to the healing and repair
process. In some cases the Dexamethasone may only have a short term
benefit to your baby or the treatment may not be successful and your baby will
need to remain on the ventilator.
Do I have to agree to this treatment?
The doctors have discussed this with you because they think that this right for
your baby to have this treatment. You do not have to agree if after this
discussion, you feel that it is not the right time for your baby to have this
treatment.
If my baby does not have the treatment now can my baby have this later?
Yes, your baby can, although the doctors will advise you when they believe is
the right time t think about giving this treatment.
Who do I ask for more information?
Please ask to speak to one of the senior doctors if you have any questions.
REFERENCES
1 Doyle LW, Davis PG, Morley CJ, et al. Low dose dexamathasone facilitates extubation among chronically ventilator-dependent infants. A multicenter international randomized control trial. Pediatrics 2006;117:75-83 2 Stark AR, Waldermar CA, Tyson JE, et al. Adverse effects of early dexamethasone treatment in extremely low birth weight infants. N Engl J Med 2001; 344: 95-101 3 T. Michael O'Shea, Jamanadas M. Kothadia, Kurt L. Klinepeter, Donald J. Goldstein, Barbara G. Jackson, and R. Grey Weaver. Randomized Placebo-controlled Trial of a 42-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, Jul 1999; 104: 15 - 21. 4 Halliday HL, Ehrenkranz RA, Doyle LW. Delayed (>3 weeks) postnatal corticosteroids for chronic lung disease in preterm infants. Cochrane Database of Systematic Reviews 2003, Issue 1. Art. No.: CD001145. DOI: 10.1002/14651858.CD001145. 5 Halliday HL, Ehrenkranz RA, Doyle LW. Moderately early (7-14 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database of Systematic Reviews 2003, Issue 1. Art. No.: CD001144. DOI: 10.1002/14651858.CD001144. 6 Steven J. Gross, Ran D. Anbar, and Barbara B. Mettelman Follow-up at 15 Years of Preterm Infants From a Controlled Trial of Moderately Early Dexamethasone for the Prevention of Chronic Lung Disease Pediatrics, Mar 2005; 115: 681 - 687. 7 T. Michael O'Shea, Lisa K. Washburn, Patricia A. Nixon, and Donald J. Goldstein. Follow-up of a Randomized, Placebo-Controlled Trial of Dexamethasone to Decrease the Duration of Ventilator Dependency in Very Low Birth Weight Infants: Neurodevelopmental Outcomes at 4 to 11 Years of Age Pediatrics, Sep 2007; 120: 594 - 602. 8 Lex W. Doyle, Peter G. Davis, Colin J. Morley, Andy McPhee, John B. Carlin and the DART Study Investigators Outcome at 2 Years of Age of Infants From the DART Study: A Multicenter, International, Randomized, Controlled Trial of Low-Dose Dexamethasone Pediatrics, Apr 2007; 119: 716 - 721.

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