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

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

Cummings 1989

N Engl J Med 1989: 320(23): 1505-1510

N Engl J Med 1989: 320(23): 1505-1510

Cummings 1989

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

No. of

Infants Mortality CLD Morbidity

Placebo

<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

– Late3 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

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?

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

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 short-term 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

L

E E

M

E

E L

M,L

Survival

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 neuro-developmental 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 1st 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