Hazards and Benefits of Postnatal Steroids David J. Burchfield, MD Professor and Chief, Neonatology University of Florida
Disclosures I have no financial affiliations or relationships to disclose. I will be discussing the off-label use of dexamethasone.
Objectives Become familiar with the history of steroid use in neonatal chronic lung disease Understand the benefits of steroid use for CLD Understand the risks of steroid use for CLD Leave with an understanding of a practical way to use post-natal steroids
Old BPD
Lung Pathology in BPD Normal BPD
Pathophysiology of BPD
Steroids to Prevent/Treat BPD Lancet June 18,1983:1356-1358
Mammel 1983 6 infants On ventilator x 4 weeks Treated with diuretics, methylxanthines, bronchodilators, fluid restriction, nutritional supplementation, and ligation of the patent ductus arteriosus Cross-over design Each infant their own control Dex or placebo x 3 days Mammel et al:lancet. 1983 Jun 18;1(8338):1356-8.
Mammel 1983 Lancet June 18,1983:1356-1358
Mammel 1983 Lancet June 18,1983:1356-1358
Mammel 1983 Lancet June 18,1983:1356-1358
Mammel 1983 The long term effects of dexamethasone treatment in neonates are not clear Infection Growth retardation Adrenal suppression Possibly neurodevelopmental compromise Lancet June 18,1983:1356-1358
Steroids to Prevent/Treat BPD
Avery Study 1985 16 infants > 2 weeks old No wean x 5 days 42 day course of dex vs placebo
Avery Study 1985
Avery 1985
Cummings 1989 N Engl J Med 1989: 320(23): 1505-1510
Cummings 1989 3 groups: Dex x 42 d Dex x 18 d Placebo > 2 weeks Rate > 15 FiO2 > 0.3 No wean x 72 h N Engl J Med 1989: 320(23): 1505-1510
Cummings 1989 N Engl J Med 1989: 320(23): 1505-1510
Cummings 1989 N Engl J Med 1989: 320(23): 1505-1510
Summary from 1980 s Dexamethasone 0.5 mg/kg BID was initial starting dose On ventilator at least 14 days with no weaning occurring prior to randomization Improvement in respiratory physiology No major impact on mortality
Early Steroids Yeh 1997 262 patients randomized <12 hr old Dex PEDIATRICS Vol. 100 No. 4 October 1997, p. e3
Yeh 1997 TABLE 3 Mortality and CLD Morbidity Placebo No. of Infants Mortality CLD Morbidity <1000 g 26 10 (38.5%) 14 (53.8%) 1000-1500 g 59 17 (28.9%) 18 (30.5%) >1500 g 45 12 (26.7%) 8 (18%) Dexamethasone <1000 g 29 13 (44.8%) 7 (24.1%)* 1000-1500 g 66 21 (31.8%) 9 (14%)* >1500 g 37 10 (27.0%) 5 (14%) * P <.05 (dexamethasone vs placebo). PEDIATRICS Vol. 100 No. 4 October 1997, p. e3
Yeh 1997 Early postnatal dexamethasone therapy, given within 12 hours after birth for 1 week and tapering over 3 weeks, Significantly reduced the incidence of CLD Permitted earlier weaning from mechanical ventilation. Transient side effects: Increase in blood glucose, BUN, and serum potassium; Increase in blood pressure and cardiac hypertrophy; Increase in parathyroid hormone and in urinary excretion of phosphate; Increase in degree of weight loss. Higher incidence of infection. No effect on ROP, IVH, head circumference, height, or bone growth. With significant, although transient, side effects of the early postnatal use of steroid and the lack of overall improvement in outcome and mortality, our recommendation regarding its routine use remains cautious until the result of a long-term follow-up study is available.
Discrepancies in Clinical Trials Age at drug administration Dose of drug Degree of illness Cross-over
Cochrane Systematic Review Evaluated the evidence at 3 ages of administration Early--< 96 hours of life 21 randomized control trials, 3072 patients Moderately early 7-14 days 7 studies, 660 total patients Late 3 weeks of life 9 trials, 562 patients Total 37 trials and 4,294 patients Halliday, HL; Ehrenkranz, RA; Doyle, LW The Cochrane Database of Systematic Reviews, Volume (4), 2006
Cochrane 2008--Early
Cochrane 2008 Early CP
CP--Early Number needed to harm=14
Conclusions of Cochrane Review Benefits Earlier extubation Decreased risks of CLD Need to treat 10 babies to prevent one case Decreased risk of death or CLD at 28 days and 36 weeks Risks Gastrointestinal bleeding, intestinal perforation, hyperglycemia, and hypertension, Long-term risks of abnormal neurological exam and cerebral palsy. Halliday, HL; Ehrenkranz, RA; Doyle, LW The Cochrane Database of Systematic Reviews, Volume (4), 2006
Halliday, HL; Ehrenkranz, RA; Doyle, LW The Cochrane Database of Systematic Reviews, Volume (4), 2006 Conclusions of Cochrane Review It appears appropriate to curtail early corticosteroid treatment for prevention of chronic lung disease. however, 448 of the 925 control infants (48%) received post-natal steroids off study Effect on survival of these control infants?
Moderately Early (7-14 days) 7 studies 660 total patients Halliday, HL; Ehrenkranz, RA; Doyle, LW : The Cochrane Library, Volume (4).2006
Moderately Early--Mortality Halliday, HL; Ehrenkranz, RA; Doyle, LW : The Cochrane Library, Volume (4).2006
Moderately Early CLD Halliday, HL; Ehrenkranz, RA; Doyle, LW : The Cochrane Library, Volume (4).2006
Moderately Early--CP Halliday, HL; Ehrenkranz, RA; Doyle, LW : The Cochrane Library, Volume (4).2006
Conclusions (7-14 Days) Benefits Reductions in failure to extubate Reduction in CLD Reduction in mortality, Risks Limited evidence concerning long term effects is provided by the trials included in this review. Halliday, HL; Ehrenkranz, RA; Doyle, LW : The Cochrane Library, Volume (4).2006
Conclusions (7-14 Days) Given the risks of short-term and potentially long-term adverse effects versus the shortterm benefits, it appears appropriate to reserve moderately early corticosteroid treatment to infants who cannot be weaned from mechanical ventilation and to minimize the dose and duration of any course of therapy. Halliday, HL; Ehrenkranz, RA; Doyle, LW : The Cochrane Library, Volume (4).2006
7-14 Days My Observations Mortality reduced at 28 days with NNT of 9 CLD decreased at 36 weeks adjusted, with NNT of 4 Mortality or CLD decreased at 36 weeks with NNT <4 No data on cross-over
Late Postnatal Steroids 3 weeks 9 trials 562 patients Halliday, HL; Ehrenkranz, RA; Doyle, LW The Cochrane Database of Systematic Reviews Volume (4), 2006
> 3 Weeks--Mortality Halliday, HL; Ehrenkranz, RA; Doyle, LW The Cochrane Database of Systematic Reviews Volume (4), 2006
> 3weeks CLD Note only one study Halliday, HL; Ehrenkranz, RA; Doyle, LW The Cochrane Database of Systematic Reviews Volume (4), 2006
Failure to extubate in 1 Week Halliday, HL; Ehrenkranz, RA; Doyle, LW The Cochrane Database of Systematic Reviews Volume (4), 2006
MDI and PDI 3 Weeks Halliday, HL; Ehrenkranz, RA; Doyle, LW The Cochrane Database of Systematic Reviews Volume (4), 2006
Cerebral Palsy Halliday, HL; Ehrenkranz, RA; Doyle, LW The Cochrane Database of Systematic Reviews Volume (4), 2006
Conclusions 3 weeks The benefits of late corticosteroid therapy may not outweigh actual or potential adverse effects. 78 of 192 control infants received steroids (40%)
Long Term Neurological Effects of Postnatal Steroids Barrington Study 8 randomized controlled trials with long term follow-up data Together, randomized 1052 infants 292 of whom are known to have died the relative risk of death is not statistically significant in any of the studies Barrington KJ: BMC Pediatr. 2001; 1: 1
Long Term Neurological Effects of Postnatal Steroids Barrington Study Survival L E E E M,L M E L Barrington KJ: BMC Pediatr. 2001; 1: 1
Long Term Neurological Effects of Postnatal Steroids Barrington Study Neurological Impairment Barrington KJ: BMC Pediatr. 2001; 1: 1
Conclusion of Barrington Study The number of premature infants who need to be treated to have one more infant with cerebral palsy (number needed to harm, NNH) is 7; To have one more infant with neurodevelopmental impairment the NNH is 11. No survival benefits
AAP Committee on Fetus and Newborn (2002) The short-term pulmonary benefits of systemic dexamethasone do not appear to confer long-term benefits. Survival does not improve after dexamethasone administration. Furthermore, data indicating an increased incidence of neurodevelopmental delay and cerebral palsy raise serious concerns about adverse long-term outcomes Pediatrics. 2002 Feb;109(2):330-8
Are we throwing out the baby with the bath water?? From early and late trials, 47% of the control infants still received rescue therapy with steroids. Studies included trials with neonates who were not at high risk of dying
A, Moderately early trial meta-regression analysis of the percentage of Open Label Glucocorticoids in the placebo group and the effect on the mortality-at-hospital-discharge outcome. Onland W et al. Pediatrics 2010;126:e954-e964 2010 by American Academy of Pediatrics
Not That Sick but almost showed survival benefit O Shea 1999 88% of Dex-treated infants survived to 1 year adjusted age, compared with 74% of placebo recipients (P =.066) FIO2 at entry Steroid 0.30-1.0 Control 0.34-1.0 Jones 1995 Collaborative trial from 31 centers 66% on ventilator 23% had an FiO2 >60%
RD (%) for death or CP among all participants versus rate of CLD (%) in the control group. Doyle L W et al. Pediatrics 2005;115:655-661 2005 by American Academy of Pediatrics
What does new study add? Only included studies after 1 st week of life Nineteen RCTs qualified for inclusion in this review These trials enrolled preterm infants who were oxygen- and/or ventilator-dependent beyond 7 days of age.
RESULTS
RESULTS
RESULTS
Summary of Benefits
Summary of Side Effects
Discussion Data on long-term neurosensory followup were available from 12 studies comprising 800 infants randomized. The significant increase in abnormal neurological examination in those randomized is of potential concern; tempered by the findings that cerebral palsy and major neurosensory disability, both overall and in survivors, were not significantly increased
Discussion Lower doses and shorter courses should be considered for these infants DART study, with a total dose of only 0.89 mg/kg over 10 days, was able to demonstrate acute benefits of extubation and reduced respiratory support. Further studies of low-dose systemic corticosteroids initiated beyond the first week of life in infants at high risk of developing BPD are also warranted
DART Trial: Kaplan-Meier survival curve for proportion failing to extubate over the 10 days of treatment. Doyle L W et al. Pediatrics 2006;117:75-83 2006 by American Academy of Pediatrics
Policy Statement Postnatal Corticosteroids to Prevent or Treat Bronchopulmonary Dysplasia High-dose dexamethasone (0.5 mg/kg per day) does not seem to confer additional therapeutic benefit over lower doses and is not recommended. Evidence is insufficient to make a recommendation regarding other glucocorticoid doses and preparations. The clinician must use clinical judgment when attempting to balance the potential adverse effects of glucocorticoid treatment with those of bronchopulmonary dysplasia Pediatrics 2010;126:800 808
Current Usage of Postnatal Steroids
Summary---Patient selection is key 1) Is the baby really sick? Develop unit-based guidelines for FiO2 and ventilator settings 2) Have you given TIME a chance? Probably should not consider until >1 week of age 3) Is the baby medically stable to receive steroids? No indomethacin, no acute infections 4) Don t overdo it dose and duration