Kristi Watterberg, MD University of New Mexico

Transcription

1 Kristi Watterberg, MD University of New Mexico

2 Dr. Watterberg has no financial or other conflicts of interest to disclose She will be discussing studies of glucocorticoids in preterm infants

3 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

4 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 O 2 (Cummings, 36 infants; NEJM 1989)

5 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

6 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

7 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)

8 Hyperglycemia Hypertension, cardiac hypertrophy Proteolysis, muscle wasting, osteopenia Sepsis Adrenal suppression GI perforation Growth failure *Neurodevelopmental impairment*

9 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

10 Sicker baby Dexamethasone Worse outcomes Sicker baby Dexamethasone Worse outcomes

11 Dex is good the more the better! All steroids are bad no babies should get them!

12 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

13 Use has declined : - NICHD 14 8% (Walsh, Pediatrics 2006) - Vt/Ox 18 10% - Canada 24 3% But (Vt/Ox data) (2002) (2004) g BW 7% 4% g BW 18% 13% g BW 29% 22%

14 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

15 Percent BPD rate Dex use Epoch 1: Epoch 2: Epoch 3: P<0.001, dex & BPD, Gestational age - Yoder, Pediatrics 2009; 124: 673

16 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

17 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) Later extubation study (n = 58) Stark, EPAS 2001; 2229 Doyle, Pediatr 2007; 119:717 But there may be another alternative

18 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

19 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

20 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

21 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

22 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

23 Crochmore, Mol Psychiatry 2005; 10:790

24 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;

25 Intubated infants, <48 o 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

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28 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

29 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

30 Infants enrolled at10 21 postnatal days Intubated, mechanically ventilated Respiratory index score (MAP x FiO 2 ) >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)

31 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

32 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

33 Lower dose DEX (<0.2mg/kg/day) may facilitate extubation Limited data suggest short- and longterm 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

34 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

35 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

36 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

37 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

38 - Lamberts et al, NEJM 337:1285, 1997

39 820 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 6.2 g/dl responded to HC Rx

40 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

41 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

42 - No Rx - HC Rx Yoder et al, Pediatr Res 51:426, 2002

43 - No Rx - HC Rx

44 Shortening fraction * VCFc = velocity of LV circumferential fiber shortening, corrected

45 RCT of HC in hypotensive ELBW 1mg/kg q 8 hours Ng, P. C. Pediatrics 2006; 117:

46 Mean Blood Pressure RCT of HC in all ELBW (PROPHET) mg/kg q 12 hours Randomization HC-treated Placebo P<0.02 AUC Day of Life

47 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

48 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/m 2 /d) Evaluate CV effects

49 Fetal origins of adult disease Perinatal origins of adult disease

50 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

51 Cardiovascular hypertension, MI, stroke Metabolic syndrome, Type II diabetes Polycystic ovary syndrome End-stage renal disease Depression

52 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

53 Glucocorticoids promote maturation Differentiation inhibit Glucocorticoids promote Cell growth & division

54 In animal models, fetal exposure to high dose steroids results in: Decreased brain weight Decreased organ weights Decreased total body weight

55 Postnatal exposure to high-dose dexamethasone in premature infants results in: Decreased weight gain Decreased head growth Decreased height at school-age

56 The ex-utero fetus

57 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 longterm adverse outcomes?

58 Cortisol nmol/l ELBW infants Fetal cortisol values Gestational age Donaldson et al Clin Endo 35:447, 1991

59 Cortisol µg/dl 50 Preemies caught between a rock and a hard place Critically ill adults and children ELBW infants 10 5 Fetal cortisol 10-90%ile range Gestational age

60 Short stature head circumference & brain volume neurodevelopmental difficulties blood pressure Other adverse outcomes in adulthood? Little work done so far, but

61 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

62 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?