Title: NEURODEVELOPMENT AND NEUROPROTECTION: VENTILATORY MANAGEMENT AND THYROID HORMONE Nigel Paneth Octobe
1NEURODEVELOPMENT AND NEUROPROTECTIONVENTILATORY
MANAGEMENT AND THYROID HORMONENigel Paneth
October 23, 2003St Peters Medical Center
2NICU SURVIVORS - VICTIMS OF MEDICAL SUCCESS
- Newborn care has been very successful in saving
the lives of preterm infants, but has made little
or no progress on saving brains.
-
- The prevalence of neurodevelopmental
disabilities among survivors has not declined
nearly enough to offset the great increase in the
number of survivors. -
3Survival of US VLBW Infants 1960 2001
4THE INCREASING PROPORTION OF CP FROM ELBW
INFANTSINNER RING 1960 0MIDDLE RING
1983 16OUTER RING 2001 25
5NEONATAL BRAIN PROTECTION TWO META-ANALYSES
- Whitelaw A Semin Neonatol. 2000 Feb5(1)33-40.
- Whitelaw A, Thoresen M Curr Opin Pediatr.
200214664-8.
- Studies are generally in term asphyxiated
infants
- Barbiturates 3 trials no significant effect
on death or disability
- Allopurinol - I trial too small to test for
death or disability
- Mild hypothermia 1 trial no adverse effects,
too small to test for death or disability
- Dexamethasone, calcium channel blockers,
magnesium sulphate - no trials yet published
6DOES VENTILATORY MANAGEMENT AFFECT LONG TERM
OUTCOME?
7FOUR VENTILATORY RISK FACTORS(NBH dataset
1,105 NJ infants
Mechanical ventilation (MV) Requiring mechanical ventilatory assistance Prolonged ventilation (P) Duration of ventilation longer than
expected for GA
Hypocapnia (C) Lowest quintile of cumulative PCO2 levels Hyperoxia (O) Highest quintile of cumulative PO2 levels Collins et al Pediatric Research 2001
50712-719
8ODDS RATIOS FOR DISABLING CP BY VENTILATORY RISK
FACTORSchildren with up to two risk factors
9ODDS RATIOS FOR DISABLING CP BY VENTILATORY RISK
FACTORSChildren with up to four risk factors
10HYPOCAPNIA MAY BE AVOIDABLE
- Hypocapnia in preterm infants (often
operationally defined as PaCO2 Hg) has been linked to adverse developmental
outcome in several studies. - Hypocapnia is usually a result of mechanical
hyperventilation, and is associated with
decreased cerebral blood flow in both human and
animal studies
11QUINTILES OF HYPOCAPNIA AND ODDS RATIO FOR
DISABLING CP IN NBH STUDY
12PERMISSIVE HYPERCAPNIAONE META-ANALYSIS
- Woodgate PG, Davies MW Permissive hypercapnia
for the prevention of morbidity and mortality in
mechanically ventilated newborn infants. Cochrane
Database Syst Rev. 2001(2)CD002061. - Two trials, neither of which showed any effect
on CNS outcomes
13MIGHT THYROID HORMONE PROTECT THE BRAIN OF THE
PREMATURE INFANT?
14EFFECTS OF NEONATAL THYROIDECTOMY IN THE RAT
- Decreased levels of several growth factors
- Decreased rate of brain protein and RNA
synthesis, via
- Decreased MRNA transcription
- Decreased ribosome synthesis
- Decreased amino acid transport into cells
- Decreased synaptogenesis via slower maturation of
brain-specific proteins D1 and D2
- Reduction in enzymes necessary for nerve terminal
development (succinic/glutamic dehydrogenase)
- Alterations in assembly of microtubule proteins
15EFFECTS OF NEONATAL THYROIDECTOMY ON MYELINATION
IN THE RAT
- Delayed synthesis of myelin precursors
- cerebroside
- sulfatide
- sphingomyelin
- Decreased synthesis of enzymes for myelin
synthesis
- MBP transferase
- 23-cyclic nucleotide 3 phosphoesterase
- galactosylceramide sulfotransferase
16THYROID HORMONE AND THE PREMATURE INFANT
- When neonatal thyroid screening began in the
1970s, premature infants frequently failed the
screen because of low total T4.
- Because TSH was not elevated, and T4 eventually
normalized, prematures with low levels of T4 were
not viewed with concern
- There is evidence however that transient
hypothyroxinemia of prematurity (THOP) may not
be benign.
17THREE LARGE STUDIES OF NEONATAL THYROID LEVELS IN
PREMATURES AND LATER DEVELOPMENT
- LUCAS TRIAL (England)
- Lucas et al Arch Dis Child 1988631201-6
- Lucas et al BMJ 19963121133-4
- 2. POPS COHORT (Holland)
- Meijer et al Arch Dis Child 1992 67944-7
- Den Ouden et al Pediatric Res 1996 39142-5
- 3. NBH COHORT (NJ)
- Reuss et al New Eng J Med 1996334821-7
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20TRANSIENT HYPOTHYROXINEMIA IN THE NBH STUDY
- Lynn Reuss linked our cohort to NJ state thyroid
screening results
- Any infant who was more than 2.6 SDs below the
mean of the batch (about 240 specimens) was
considered to have severe THOP
- 15 of babies 4.4 µg/L
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22RISK OF CEREBRAL PALSY IN RELATION TO TRANSIENT
HYPOTHYROXINEMIA (HT)IN NBH STUDY
23BAYLEY SCORES IN RELATION TO TRANSIENT
HYPOTHYROXINEMIA (HT) IN NBH STUDY
24ODDS OF CP IN RELATION TO SEVERE HT BEFORE AND
AFTER STATISTICAL ADJUSTMENTS IN NBH STUDY
25STUDIES OF NEONATAL EFFECTS OF THYROID
SUPPLEMENTATION DESIGNS
26STUDIES OF NEONATAL EFFECTS OF THYROID
SUPPLEMENTATIONRESULTS
27STUDIES OF LATE EFFECTS OF THYROID
SUPPLEMENTATION DESIGN
28STUDIES OF LATE EFFECTS OF THYROID
SUPPLEMENTATION RESULTS
29INTERNATIONAL PILOT STUDY TO ASCERTAIN BEST
THYROID HORMONE DOSING SCHEDULE IN INFANTS 23-28
WEEKS(FUNDED BY NINDS)
- Treatment sites
- New York Medical College (lead institution)
- Edmund LaGamma, PI
- Amsterdam Medical Center
- Aleid Van Wassenaar, PI
- Hospital La Paz-Autonomous University of Madrid
- Gabriella Morealle de Escobar, PI
- Data Center
- Michigan State University
- Nigel Paneth, PI
30DOSAGE SCHEDULES IN SIX GROUPS OF 24 INFANTS OF
23-28 WEEKS GA
- Control
- Iodine only
- 4 µg/kg/day T4 by continuous infusion
- 8 µg/kg/day T4 by continuous infusion
- 4 µg/kg/day T4 in a single bolus dose
- 8 µg/kg/day T4 in a single bolus dose
- (All four thyroid treatment groups will also
receive 6 µg/kg/day T3 for first 7 days)
31MEASUREMENTS TO BE MADE
- From the mother as close as possible to time of
delivery Plasma T4, FT4, TSH, urinary iodine
- From the infant Plasma T4, FT4, TSH, T3, TBG,
and urinary iodine on days 0, 3, 7, 14, 21, 42,
56 and at hospital discharge
- T4, T3 , Cortisol by Radioimmunoassay
- TSH, TBG by Immunochemiluminometric assay
- FT4 by Direct equilibrium dialysis
32NEXT STEP
- Once we establish the most appropriate manner
of normalizing thyroid hormone profiles in
prematures, we hope to do an international study
of thyroid supplementation with the endpoint
being disabling cerebral palsy and cognitive
skills at age two. - Please let me know if you are interested in
participating! (paneth_at_msu.edu)
33SUMMARY
- We have no established pharmacologic means of
protecting the brain in either preterm or term
newborns, but we do have at least one reasonable
intervention and one promising research effort. - The reasonable intervention is to minimize
exposure to hypocapnia (keeping PaCO2 above 35 mm
Hg).
- The promising research effort is to see whether
thyroid supplementation in the first weeks of
life may be neuroprotective.