Hazards and Benefits of Postnatal Steroids. David J. Burchfield, MD Professor and Chief, Neonatology University of Florida

Transcription

1 Hazards and Benefits of Postnatal Steroids David J. Burchfield, MD Professor and Chief, Neonatology University of Florida

2 Disclosures I have no financial affiliations or relationships to disclose. I will be discussing the off-label use of dexamethasone.

3 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

4 Old BPD

5 Lung Pathology in BPD Normal BPD

6 Pathophysiology of BPD

7 Steroids to Prevent/Treat BPD Lancet June 18,1983:

8 Mammel 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 Jun 18;1(8338):

9 Mammel 1983 Lancet June 18,1983:

10 Mammel 1983 Lancet June 18,1983:

11 Mammel 1983 Lancet June 18,1983:

12 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:

13 Steroids to Prevent/Treat BPD

14 Avery Study infants > 2 weeks old No wean x 5 days 42 day course of dex vs placebo

15

16 Avery Study 1985

17 Avery 1985

18 Cummings 1989 N Engl J Med 1989: 320(23):

19 Cummings 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):

20 Cummings 1989 N Engl J Med 1989: 320(23):

21 Cummings 1989 N Engl J Med 1989: 320(23):

22 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

23 Early Steroids Yeh patients randomized <12 hr old Dex PEDIATRICS Vol. 100 No. 4 October 1997, p. e3

24 Yeh 1997 TABLE 3 Mortality and CLD Morbidity Placebo No. of Infants Mortality CLD Morbidity <1000 g (38.5%) 14 (53.8%) g (28.9%) 18 (30.5%) >1500 g (26.7%) 8 (18%) Dexamethasone <1000 g (44.8%) 7 (24.1%)* g (31.8%) 9 (14%)* >1500 g (27.0%) 5 (14%) * P <.05 (dexamethasone vs placebo). PEDIATRICS Vol. 100 No. 4 October 1997, p. e3

25 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.

26 Discrepancies in Clinical Trials Age at drug administration Dose of drug Degree of illness Cross-over

27 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

28 Cochrane Early

29 Cochrane 2008 Early CP

30 CP--Early Number needed to harm=14

31 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

32 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?

33 Moderately Early (7-14 days) 7 studies 660 total patients Halliday, HL; Ehrenkranz, RA; Doyle, LW : The Cochrane Library, Volume (4).2006

34 Moderately Early--Mortality Halliday, HL; Ehrenkranz, RA; Doyle, LW : The Cochrane Library, Volume (4).2006

35 Moderately Early CLD Halliday, HL; Ehrenkranz, RA; Doyle, LW : The Cochrane Library, Volume (4).2006

36 Moderately Early--CP Halliday, HL; Ehrenkranz, RA; Doyle, LW : The Cochrane Library, Volume (4).2006

37 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

38 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

39 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

40 Late Postnatal Steroids 3 weeks 9 trials 562 patients Halliday, HL; Ehrenkranz, RA; Doyle, LW The Cochrane Database of Systematic Reviews Volume (4), 2006

41 > 3 Weeks--Mortality Halliday, HL; Ehrenkranz, RA; Doyle, LW The Cochrane Database of Systematic Reviews Volume (4), 2006

42 > 3weeks CLD Note only one study Halliday, HL; Ehrenkranz, RA; Doyle, LW The Cochrane Database of Systematic Reviews Volume (4), 2006

43 Failure to extubate in 1 Week Halliday, HL; Ehrenkranz, RA; Doyle, LW The Cochrane Database of Systematic Reviews Volume (4), 2006

44 MDI and PDI 3 Weeks Halliday, HL; Ehrenkranz, RA; Doyle, LW The Cochrane Database of Systematic Reviews Volume (4), 2006

45 Cerebral Palsy Halliday, HL; Ehrenkranz, RA; Doyle, LW The Cochrane Database of Systematic Reviews Volume (4), 2006

46 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%)

47 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

48 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

49 Long Term Neurological Effects of Postnatal Steroids Barrington Study Neurological Impairment Barrington KJ: BMC Pediatr. 2001; 1: 1

50 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

51 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 Feb;109(2):330-8

52 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

53 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-e by American Academy of Pediatrics

54 Not That Sick but almost showed survival benefit O Shea % of Dex-treated infants survived to 1 year adjusted age, compared with 74% of placebo recipients (P =.066) FIO2 at entry Steroid Control Jones 1995 Collaborative trial from 31 centers 66% on ventilator 23% had an FiO2 >60%

55 RD (%) for death or CP among all participants versus rate of CLD (%) in the control group. Doyle L W et al. Pediatrics 2005;115: by American Academy of Pediatrics

56

57 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.

58 RESULTS

59 RESULTS

60 RESULTS

61 Summary of Benefits

62 Summary of Side Effects

63 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

64 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

65 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: by American Academy of Pediatrics

66 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:

67 Current Usage of Postnatal Steroids

68 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