NEURODEVELOPMENT AND NEUROPROTECTION: VENTILATORY MANAGEMENT AND THYROID HORMONE Nigel Paneth Octobe - PowerPoint PPT Presentation

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NEURODEVELOPMENT AND NEUROPROTECTION: VENTILATORY MANAGEMENT AND THYROID HORMONE Nigel Paneth Octobe

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Title: NEURODEVELOPMENT AND NEUROPROTECTION: VENTILATORY MANAGEMENT AND THYROID HORMONE Nigel Paneth Octobe


1
NEURODEVELOPMENT AND NEUROPROTECTIONVENTILATORY
MANAGEMENT AND THYROID HORMONENigel Paneth
October 23, 2003St Peters Medical Center
  •  

2
NICU 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.

3
Survival of US VLBW Infants 1960 2001
4
THE INCREASING PROPORTION OF CP FROM ELBW
INFANTSINNER RING 1960 0MIDDLE RING
1983 16OUTER RING 2001 25
5
NEONATAL 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

6
DOES VENTILATORY MANAGEMENT AFFECT LONG TERM
OUTCOME?
7
FOUR 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

  • 8
    ODDS RATIOS FOR DISABLING CP BY VENTILATORY RISK
    FACTORSchildren with up to two risk factors
    9
    ODDS RATIOS FOR DISABLING CP BY VENTILATORY RISK
    FACTORSChildren with up to four risk factors
    10
    HYPOCAPNIA 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

    11
    QUINTILES OF HYPOCAPNIA AND ODDS RATIO FOR
    DISABLING CP IN NBH STUDY
    12
    PERMISSIVE 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

    13
    MIGHT THYROID HORMONE PROTECT THE BRAIN OF THE
    PREMATURE INFANT?
    14
    EFFECTS 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

    15
    EFFECTS 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

    16
    THYROID 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.

    17
    THREE 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

    18
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    19
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    20
    TRANSIENT 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

    21
    (No Transcript)
    22
    RISK OF CEREBRAL PALSY IN RELATION TO TRANSIENT
    HYPOTHYROXINEMIA (HT)IN NBH STUDY
    23
    BAYLEY SCORES IN RELATION TO TRANSIENT
    HYPOTHYROXINEMIA (HT) IN NBH STUDY
    24
    ODDS OF CP IN RELATION TO SEVERE HT BEFORE AND
    AFTER STATISTICAL ADJUSTMENTS IN NBH STUDY
    25
    STUDIES OF NEONATAL EFFECTS OF THYROID
    SUPPLEMENTATION DESIGNS
    26
    STUDIES OF NEONATAL EFFECTS OF THYROID
    SUPPLEMENTATIONRESULTS
    27
    STUDIES OF LATE EFFECTS OF THYROID
    SUPPLEMENTATION DESIGN
    28
    STUDIES OF LATE EFFECTS OF THYROID
    SUPPLEMENTATION RESULTS
    29
    INTERNATIONAL 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

    30
    DOSAGE 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)

    31
    MEASUREMENTS 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

    32
    NEXT 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)

    33
    SUMMARY
    • 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.
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