Kristi Watterberg, MD

University of New Mexico

Dr. Watterberg has no financial or other conflicts of interest to disclose

She will be discussing studies of glucocorticoids in preterm infants

History – how did we get here?

Where is here? – current information

◦ Dexamethasone for BPD

◦ Hydrocortisone for BPD

◦ Hydrocortisone for early hypotension

Reasons to worry

◦ Immediate side effects

◦ Growth and development

◦ Very long term outcomes

Abstracts: early anecdotes

(„78, „80, „81)

„hastened weaning from ventilator‟

(Mammel, 6 infants; Lancet, 1983)

„striking short-term improvement‟

(Avery, 16 infants; Pediatrics, 1985)

faster weaning from IMV and O2

(Cummings, 36 infants; NEJM 1989)

“The long term effects are not clear . . . Potential complications of glucocorticoid treatment are well known [including] possibly long term neurodevelopmental compromise . . . The treatment cannot be recommended without further study of patient selection, dosage schedules, short and long-term side effects, and the mechanisms of its actions.”

--Mammel, Lancet 1983

High dose – 0.5mg/kg/day

(Prenatal: 12mg/day to mothers 0.15mg/kg)

Long-term – 42 day tapering course

(Prenatal: 2 days, ± weekly repeat)

Started earlier and earlier in life, until…

Rx works (Yeh , Pediatrics 100:(4)E3,1997)

Or it doesn‟t (Sinkin, Pediatrics 105:542, 2000)

Rx works, but dose for adverse effect

(Garland, Pediatrics, 104:91, 1999)

Study stopped for lack of efficacy and/or safety concerns

(Vt-Ox, Pediatrics 108:741, 2001)

(NICHD, NEJM 344:95, 2001)

Hyperglycemia

Hypertension, cardiac hypertrophy

Proteolysis, muscle wasting, osteopenia

Sepsis

Adrenal suppression

GI perforation

Growth failure

*Neurodevelopmental impairment*

Dex is associated with ↑CP & neurologic impairment

Meta-analysis of >1000 patients in RCTs

Barrington KJ, BMC Pediatrics 1:1, 2001

Dex is a risk factor for MDI <70 & abnormal neurologic exam

Follow up of > 1100 ELBW infants, cohort study

NICHD Neonatal Network, Pediatrics 105:1216, 2000

Sicker baby Dexamethasone Worse

outcomes

Sicker baby

Dexamethasone

Worse outcomes

All steroids are

bad – no babies

should get them!

Dex is good – the

more the better!

BPD, extubation failure, no mortality

Many short and long-term complications

Routine use . . . is not recommended

Outside the context of a randomized trial, use of corticosteroids should be limited to exceptional clinical circumstances

Parents should be fully informed about risks

◦ Pediatrics109:330; 2002

Use has declined : - NICHD 14 8%

(Walsh, Pediatrics 2006) - Vt/Ox 18 10%

- Canada 24 3%

But (Vt/Ox data) (2002) (2004)

◦ 1000 – 1250g BW 7% 4%

◦ 750 – 999g BW 18% 13%

◦ 500 – 749g BW 29% 22%

BPD may be rising in incidence and/or severity with decreasing use of PNS

◦ Population study (Israel): ↓PNS, ↑BPD

- Shinwell, Arch Dis Child 2007; 92:F30

◦ Single center cohort: ↓PNS, ↑vent dependence

- Kobaly - Pediatrics 2008;121:73

◦ Pediatrix (77,520 babies <32 weeks EGA): ↓PNS, ↑ BPD in babies <29 weeks,↑ severe BPD overall

- Yoder Pediatrics 2009; 124:673

- Yoder, Pediatrics 2009; 124: 673

Epoch 1: ’97 – ’99

Epoch 2: ‘00 – ’03

Epoch 3: ‘04 – ’06

P<0.001, dex & BPD,

Gestational age

Per

cen

t

BPD rate

Dex use

BPD: ↑ incidence of Bayley MDI & PDI <70, abnormal neurologic exam

◦ (NICHD network, 1154 ELBW infants)

Balancing the risk – RCT “meta-regression”

◦ If the baseline risk for BPD in the study population

was low (35%), dex ↑ risk of death/CP

◦ If the risk was >50%, dex ↓ risk of death/CP

Doyle, Pediatrics 2005; 115:794

Decreasing the dex dose might also help

Most previous studies started with a dose of 0.5mg/kg/day

Lower doses (0.15mg/kg/day) were not associated with adverse neurodevelopmental outcomes in 2 studies

Early Rx (n=123)

Stark, EPAS 2001; 2229

Later extubation study (n = 58)

Doyle, Pediatr 2007; 119:717

But there may be another alternative…

Dexamethasone is

◦ Synthetic

◦ Contains preservative

◦ Lacks mineralocorticoid activity

◦ Suppresses endogenous cortisol synthesis

◦ Has a far longer half life than hydrocortisone

◦ Is many times more potent than cortisol

May be as much as 150x more powerful d/t amplifying effect of its prolonged half-life

Meikle, Am J Med 1977

Hydrocortisone is

◦ Identical to native cortisol

◦ Can be obtained without preservative

◦ Provides mineralocorticoid activity

◦ May suppress HPA axis at high doses, but does not do so at lower doses

First premise: at high doses ALL glucocorticoids impair growth as a natural consequence of their actions.

◦ They suppress cell growth and proliferation

◦ They promote differentiation, or “maturation”

◦ Therefore, high doses given to fetal or neonatal animals result in growth impairment

2 types of steroid receptors in the brain: mineralocorticoid and glucocorticoid

Both in high density in the hippocampus – an area of the brain critical to learning and memory

Under basal conditions, cortisol binds primarily to mineralocorticoid receptors

Under stressful conditions, cortisol also binds to glucocorticoid receptors

Dex suppresses cortisol production (producing a “chemical adrenalectomy”) and binds ONLY to glucocorticoid receptors

Cortisol deficiency (adrenalectomy) in adult animals leads to neuronal apoptosis in the hippocampus

Dexamethasone also leads to neuronal apoptosis in both adrenalectomized & control animals

Corticosterone (=cortisol in rats) protects animals from DEX-induced apoptosis

Crochmore, Mol Psychiatry 2005; 10:790

Preemies have hippocampal volume on MRI Isaacs Pediatr Res 2001; 47:713

Preemies treated with dex have hippocampal volume vs. controls (small cohort studies)

Murphy Pediatr 2001; 107:217

Parikh Pediatr 2007;119:265

Preemies treated with HC have no reduction in volume or increase in lesions vs. untreated controls (large cohort study & RCT)

Rademaker, J Pediatr 2007; 150:351

Parikh, EPAS2009; 3212.2

Intubated infants, <48o of age

HC 1–2mg/kg/day tapered over 12–15d

◦ Watterberg (n=40): survival w/o BPD

◦ Watterberg (n=360): no significant benefit

◦ Peltoniemi (n=51): 64% vs. 46% - NS

◦ Bonsante (n=50): survival w/o BPD

Meta-analysis (3 studies): no adverse effects

Peltoniemi, Neonatology 2009;95:240

Follow up of the multicenter trial (n=252):

◦ No adverse effects, growth or neurodevelopment

◦ Possible benefits of HC Rx:

Fewer babies with MDI <70 on Bayley II scales

More babies had attainment of object permanence –early measure of pre-frontal cortex development

Watterberg, Pediatrics 2007; 120: 40

Cohort studies of later, higher dose (5mg/kg/d tapered over 22 days)

◦ = DEX for extubation and FiO2, fewer acute adverse effects (25HC, 23dex)

Lodygensky Acta Paediatr 2003; 92:827

◦ No differences between HC-treated and larger, more mature, less sick comparison group on functional/structural outcomes at up to 8-10 years of age (62HC, 164 control)

Rademaker J Pediatr 2007; 150:351

Infants enrolled at10 – 21 postnatal days

◦ Intubated, mechanically ventilated

◦ Respiratory index score (MAP x FiO2) >2

HC: 3mg/kg/day tapered over 7 days

No mandatory extubation specified

Survival w/o severe BPD: 3/31(10%) vs 5/33(16%)

Volumetric MRI – no adverse effect of HC

Parikh (abstract, PAS 2009)

“the benefits…especially dex, may not outweigh the risks” ◦ Facilitates extubation, BPD, but adverse effects

GI perforation

Hyperglycemia, hypertension

Hypertrophic cardiomyopathy

Growth failure

Increased cerebral palsy, abnormal neurologic exam

“a compelling need for long term follow up”

HC – few positive or negative effects

Halliday/Ehrenkranz/Doyle, Cochrane review 2009

High dose DEX (0.5mg/kg/day) associated with numerous adverse effects

There is no basis for postulating that such high doses confer additional benefit over lower dose therapy

Meta-analysis concluded cumulative dose may BPD w/o adverse neurodevelopment

Onland, Pediatrics 2009; 123:367

But: RCTs comparing higher/lower daily doses have not shown benefit from higher doses

This therapy cannot be recommended

Lower dose DEX (<0.2mg/kg/day) may facilitate extubation

Limited data suggest short- and long-term adverse effects vs. higher dose

Additional RCTs that include long-term assessment of neurodevelopmental outcomes are warranted

Pending additional data, Rx cannot be clearly recommended

RCTs: Early HC may survival w/o BPD

Cohort data: later therapy may extubation

Long-term neurodevelopmental outcomes are reassuring

Further RCTs of both early and later HC are warranted, to

◦ Target populations that may derive most benefit

◦ the incidence of spontaneous GI perforation

◦ Assess the efficacy of later HC therapy to facilitate extubation

Awaiting further studies, clinicians must balance

◦ the known adverse effects of BPD with

◦ the potential adverse effects of treatments

“it appears prudent to reserve the use of late corticosteroids to infants who cannot be weaned from mechanical ventilation and to minimize the dose and duration of any course of treatment”

Halliday/Ehrenkranz/Doyle, Cochrane Database 2009

After discussing with the parents

Based on the limited available evidence, the clinician might consider the lowest dose and shortest course of DEX shown to be efficacious, or a similar course of HC, e.g.

◦ 0.15mg/kg/day DX (Doyle Pediatr 2006; 117:75)

◦ 4 – 6 mg/kg/day HC

◦ tapered over 10 days

What are we trying to achieve?

◦ Treatment of relative adrenal insufficiency

- Defined as cortisol values inappropriately low for the degree of stress/illness, together with cardiovascular dysfunction/shock

◦ Or, possibly, a pharmacologic effect of HC on cardiovascular system

- Lamberts et al, NEJM 337:1285, 1997

820 gram 26 week EGA infant

Initially did well on low ventilator settings after surfactant, extubated to CPAP day 3

Deteriorated day 8, re-intubated, dx PDA

Indomethacin Rx x 2, failed, ligated D14

Post-op: hypotension, poor perfusion, decreased urine output

Cortisol 6.2g/dl – responded to HC Rx

Infants on dopamine have ↓basal and stimulated cortisol

Scott & Watterberg, Pediatr Res 37:112, 1995

Ng et al Arch Dis Child 89:F119, 2004

Arterial BP correlates with cortisol production

Arnold et al, Pediatric Res 44: 876, 1998

↓ cortisol production correlates with poor CV function in premature baboons

Yoder et al, Pediatr Res 51:426, 2002

San Antonio group – 125d baboons have “impaired CV function early in life”

~ 2/3 given volume & inotropic support

Some are refractory, but respond to HC

They decided to study cortisol production and CV function

–Yoder et al, Pediatr Res 51:426, 2002

- No Rx

- HC Rx

- No Rx

- HC Rx

* VCFc = velocity of LV circumferential

fiber shortening, corrected Shortening fraction

Ng, P. C. Pediatrics 2006; 117:367-375

RCT of HC in hypotensive ELBW

1mg/kg q 8 hours

RCT of HC in all ELBW (PROPHET)

50

45

40

35

30

20

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

Mea

n B

loo

d P

ress

ure

Day of Life

HC-treated

Placebo

P<0.02 AUC Randomization

0.5mg/kg q 12 hours

Low values seen in critically ill patients

Associated with cardiovascular dysfunction

◦ But…

Concern about short and long term effects of prematurely elevated cortisol values

Interaction with other drugs – indomethacin

“Need additional studies”

HC may be more appropriate for relative AI than high dose vasopressors, but…

◦ Very prolonged half-life

(adults, <2 hours; ELBW infants, mean 8-13 hours)

◦ Doses of 3 – 6 mg/kg/day may lead to very high serum levels

Perhaps, draw a cortisol level, then

◦ Try a test dose of 1 mg/kg

◦ Dose of 0.5mg/kg q 12 hours (~8-10mg/m2/d)

◦ Evaluate CV effects

“Fetal” origins of adult disease

Perinatal origins of adult disease

Many developmental events occur during a specific window of opportunity

Changing the environment in that window may permanently change outcomes.

Low birth weight in term infants has been linked to a variety of adult diseases

Cardiovascular – hypertension, MI, stroke

Metabolic syndrome, Type II diabetes

Polycystic ovary syndrome

End-stage renal disease

Depression

The „thrifty gene‟ hypothesis:

◦ malnutrition in utero changes in gene expression to adapt to relative starvation

◦ adaptive in utero, maladaptive when food is plentiful

◦ may be analogous to exposure of subsistence cultures to modern abundance of food

Linked with fetal exposure to excess cortisol

Glucocorticoids promote “maturation”

Cell growth &

division

Differentiation

Glucocorticoids inhibit promote

In animal models, fetal exposure to high dose steroids results in:

◦ Decreased brain weight

◦ Decreased organ weights

◦ Decreased total body weight

Postnatal exposure to high-dose dexamethasone in premature infants results in:

◦ Decreased weight gain

◦ Decreased head growth

◦ Decreased height at school-age

“The ex-utero fetus”

They have no choice – increased cortisol is necessary to survive under stress

And cortisol is necessary to control inflammation.

But . . . could increased exposure to cortisol contribute to some of their long-term adverse outcomes?

Donaldson et al Clin Endo 35:447, 1991

Cort

isol

nm

ol/

L

ELBW infants

Fetal cortisol

values

24 28 32 36 40

Gestational age

Cort

isol

µg/d

l

20 24 28 32 36 40

Gestational age

5

50

25

10

15

Critically ill adults and children

ELBW infants

Fetal cortisol 10-90%ile range

Preemies – caught between a rock and a hard place

Short stature

head circumference & brain volume

neurodevelopmental difficulties

blood pressure

Other adverse outcomes in adulthood?

◦ Little work done so far, but…

50 children tested at 4 – 10 years of age

Born at ≤ 32 weeks (38 AGA, 12 SGA)

Insulin sensitivity (x10-4/min-

1[mU/liter])

◦ term AGA infants: 21.6

◦ term SGA infants: 15.1

◦ Preterm AGA/SGA: 14.2/12.9 (p<0.01 vs control)

◦ Hofman et al, NEJM 351:2179, 2004

Exogenous glucocorticoid:

◦ Strong medicine

◦ Powerful side effects

◦ Randomized trials with long term follow-up are essential to assess risk/benefit

Endogenous glucocorticoid:

◦ Preterm infants have exposure vs. fetus

◦ May affect long term outcomes

◦ Could decreasing stress in the nursery improve outcomes?