NEURODEVELOPMENT AND NEUROPROTECTION:
VENTILATORY MANAGEMENT AND THYROID HORMONE
Nigel Paneth October 23, 2003
St Peters Medical Center
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.
Survival of US VLBW Infants 1960 – 2001
0%
42% 46%
85%
70%
94%
00.10.20.30.40.50.60.70.80.9
1
% survival
1960 1983 2001
0.5-1.0 kg1-1.5 kg
THE INCREASING PROPORTION OF CP FROM ELBW INFANTS
INNER RING – 1960 – 0%MIDDLE RING – 1983 – 16%OUTER RING – 2001 – 25%
0%
100%
16%
84%
25%
75%
< 1,000 g> 1,000 g
NEONATAL BRAIN PROTECTION: TWO META-ANALYSES
1. Whitelaw A: Semin Neonatol. 2000 Feb;5(1):33-40.2. Whitelaw A, Thoresen M: Curr Opin Pediatr.
2002;14:664-8.
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
DOES VENTILATORY MANAGEMENT AFFECT LONG
TERM OUTCOME?
FOUR VENTILATORY RISK FACTORS
(NBH dataset – 1,105 NJ infants < 2kg)
• 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; 50:712-719
ODDS RATIOS FOR DISABLING CP BY VENTILATORY RISK FACTORS:children with up to two risk factors
1
2.72
4.2
7.1
0
1
2
3
4
5
6
7
8
no riskMV onlyMV + OMV + CMV + P
ODDS RATIOS FOR DISABLING CP BY VENTILATORY RISK FACTORS:
Children with up to four risk factors
0
10
20
30
40
50
60
no risk factorsMV onlyMV + 0MV + C MV + PMV + COMV + CPMV + OPMV + COP
HYPOCAPNIA MAY BE AVOIDABLE
Hypocapnia in preterm infants (often operationally defined as PaCO2 < 25 or < 35 mm 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
QUINTILES OF HYPOCAPNIA AND ODDS RATIO FOR DISABLING CP IN
NBH STUDY
1 1.1
2 2.1
5.3
0
1
2
3
4
5
6
Quintiles of PCO2
Q1 - HIGHQ2Q3Q4Q5 - LOW
PERMISSIVE HYPERCAPNIA:ONE 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
MIGHT THYROID HORMONE PROTECT THE BRAIN OF THE
PREMATURE INFANT?
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
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– 2’3’-cyclic nucleotide 3’ phosphoesterase– galactosylceramide sulfotransferase
THYROID HORMONE AND THE PREMATURE INFANT
• When neonatal thyroid screening began in the 1970’s, 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.
THREE LARGE STUDIES OF NEONATAL THYROID LEVELS IN PREMATURES AND
LATER DEVELOPMENT
1. LUCAS TRIAL (England)• Lucas et al Arch Dis Child 1988;63:1201-6
• Lucas et al BMJ 1996;312:1133-4 2. POPS COHORT (Holland)• Meijer et al Arch Dis Child 1992; 67:944-7• Den Ouden et al Pediatric Res 1996; 39:142-5
3. NBH COHORT (NJ)• Reuss et al New Eng J Med 1996;334:821-7
226 < 1,850 gSample size
No difference (only 13 CP cases)
Neurological deficits
6.6 points lower WISC* IQ (age 8)
Cognitive Results in childhood
8.3 points lowerBayley* IQ (18 mos)
Cognitive Results in infancy
T3 < 0.3nM/L
(20% of study population)
Definition of THOP
EnglandLocation
944 < 1,500 g + < 32 weeks
Sample size
30% ↑ in age 5 neurologic dysfunction per SD ↓ in T4
Neurological deficits
30% increase in age 9 school failure for each SD
decline in T4
Cognitive Results in childhood
Three times more likely to fail national screening test
Cognitive Results in infancy
T4 < 3 SD’s below mean
(30% of study population) Definition of THOP
HollandLocation
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 < 33 weeks had THOP; mean T4 was 4.4 µg/L
N = 466 < 2,000gSample size
3.6-4.4-fold increased risk of CP at age 2.
4.9 times less likely to walk at age 6
Neurological deficits
8.4 points lower Stanford-Binet IQ at age 6.
Cognitive Results in childhood
6.8 points lower Bayley IQ at 24 months
Cognitive Results in infancy
T4 < 2.6 SD’s below mean(15% of population)
Definition of THOP
USA Location
RISK OF CEREBRAL PALSY IN RELATION TO TRANSIENT HYPOTHYROXINEMIA (HT)
IN NBH STUDY
0%
5%
10%
15%
20%
25%
30%
35%
22-27weeks
28-29weeks
30-31weeks
32-33weeks
From Reuss et al NEJM 1996;334:821-7
HT presentHT absent
BAYLEY SCORES IN RELATION TO TRANSIENT HYPOTHYROXINEMIA (HT) IN NBH
STUDY
50
60
70
80
90
100
110
22-27weeks
28-29weeks
30-31weeks
32-33weeks
From Reuss et al NEJM 1996;334:821-7
HT presentHT absent
ODDS OF CP IN RELATION TO SEVERE HT BEFORE AND AFTER STATISTICAL ADJUSTMENTS
IN NBH STUDY
6.8 (0.3-13.2)4.4 (1.0-18.6)Adjusted for GA and 21 other
variables
9.9 (3.0-16.9)3.5 (0.9-13.6)Adjusted for GA and 15 other
variables
15.4 (8.1-22.6)10.8 (3.0-39.3)Adjusted for gestational age
17.5 (10.7-24.3)17.6 (5.0-16.7)Unadjusted
MDI SCORE DIFFERENCES
ODDS RATIO FOR CP
STUDIES OF NEONATAL EFFECTS OF
THYROID SUPPLEMENTATION: DESIGNS
20 µg/kg T4 x 2 weeks
< 31 weeks20Van Hole 1987
50 µg T3 x 2 days< 32 weeks22Amato 1989
50 µg T4 at 1h and 24 h
< 34 weeks18 Amato 1988
25 µg T4 +
5 µg T3 for neonatal stay
< 37 wks or < 2,200 g
44,55Schonberger 1981
DOSESUBJECTS N PER ARM
STUDY
STUDIES OF NEONATAL EFFECTS OF THYROID SUPPLEMENTATION:RESULTS
No effect on HR, FIO2, weight gain
Van Hole 1987
Peak FIO2 58% in treated, 78% in controls (p < .05)
1.0Amato 1989
No effect on peak FIO2 1.0Amato 1988
RR = 0.65 for mechanical vent. or CPAP (p < .05)
0.23 (p < .05)Schonberger 1981
Other effects of treatmentRR for mortality in
treated arm
STUDY
STUDIES OF LATE EFFECTS OF THYROID SUPPLEMENTATION: DESIGN
< 30 weeks
26-28 wks
SUBJECTS
8 µg T4/kg x 6 weeks
100Van Wassenaer 1997
10-15 µg T4/kg X 6-7 weeks
11,12Chowdry 1984
DOSAGEN PER ARM
STUDY
STUDIES OF LATE EFFECTS OF THYROID SUPPLEMENTATION: RESULTS
No effect on sepsis, FIO2, PDA or US brain lesions.
RR for abnormal neurologic outcome at 18 mos = 0.53 (NS)
No effect on growth
Other effects of treatment
Bayley MDI
–3.4 in all treated (NS), but +18 in subjects < 27 wks (p < .01)
0.67 (NS)Van Wassenaer 1997
Bayley
MDI +11.4 (NS)
0.45 (NS)Chowdry 1984
IQ difference
RR for mortality
STUDY
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
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)
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
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! ([email protected])
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.