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! (paneth@msu.edu)

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.