Brain Injury in Premature Brain Injury in Premature Infants: The Role of Cerebral Infants: The Role of Cerebral

AutoregulationAutoregulation

Jeffrey R. Kaiser, MD, MAJeffrey R. Kaiser, MD, MAPediatrics, Neonatology

UAMS College of MedicineLittle Rock, AR

Perinatal ConferenceFebruary 17, 2005

BackgroundBackground

Advances in obstetric & newborn intensive care over the last 4 decades have led to dramatic improvements in survival for the most premature of infants

Sick VLBW Infant

Prematurity & Brain InjuryPrematurity & Brain Injury

• The immaturity of the premature infant’s brain makes it inherently more vulnerable to injury

• The more premature, the greater the chance of brain damage

→→

The Magnitude of the Problem The Magnitude of the Problem of Brain Injury in VLBW Infantsof Brain Injury in VLBW Infants

More VLBW infants at risk of developing severe brain injury are now surviving– Large absolute number of VLBW infants

affected (>55,000/year in U.S.)– High survival rates (>85%)

– 15% of VLBW infants with severe brain injury

Causes of Brain Injury in Causes of Brain Injury in the Premature Infantthe Premature Infant

Multifactorial– Vascular:

• Immature thin & fragile blood vessels can easily rupture

– Extravascular:• Poor support for the blood vessels

– IntravascularIntravascular::• Blood clotting problems• Disturbed regulation of CBF & BP

Cerebral AutoregulationCerebral Autoregulation

• Maintains constant blood flow to the brain despite wide changes in BP

• Narrowing or dilation of terminal cerebral arterioles

• Present in healthy adults, term newborns, fetal & neonatal lab animals 0

20

40

60

80

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140

20 40 60 80 100

Autoregulatory Plateau

Lower Limit

Upper Limit

Mean Carotid Arterial Blood Pressure (mm Hg)

CB

F (m

l•100

gm

-1m

in-1

)

0

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40

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140

20 40 60 80 100

Autoregulatory Plateau

Lower Limit

Upper Limit

Mean Carotid Arterial Blood Pressure (mm Hg)

CB

F (m

l•100

gm

-1m

in-1

)

Intact

Cerebral Autoregulation in Cerebral Autoregulation in Premature InfantsPremature Infants

• Cerebral autoregulation is generally considered impaired in sick premature infants (Lou, 1979)

• Many premature newborns, however, have intact cerebral autoregulation(Kaiser, 2004, Tsuji, 2002)

Pressure Passive(Impaired)

SignificanceSignificance

If the pattern of cerebral autoregulation can be understood, then interventions to control fluctuations of BP, CBF, &

ABGs could be implemented for VLBW infants in the hopes of preventing

subsequent brain injury & long-term neurodevelopmental disability

Determination of Cerebral Determination of Cerebral Autoregulatory CapacityAutoregulatory Capacity

• Instantaneous changes in CBF are compared to changes in BP after routine neonatal care procedures

• Adult tests too invasive• Surfactant therapy & endotracheal

tube suctioning

Experimental ProtocolExperimental Protocol

• Ventilated VLBW infants during the 1st week, no ultrasound evidence of brain injury prior to the study or major congenital anomalies

• Baseline continuous monitoring of BP, O2, CO2, & CBF (~15 min)

• Surfactant administration or ETT suctioning• Monitoring ≥ 45 min

Surfactant Administration Surfactant Administration Acutely Affects Cerebral Acutely Affects Cerebral

Hemodynamics in VLBW InfantsHemodynamics in VLBW Infants

Kaiser JR, Gauss CH, Williams DK. Journal of Pediatrics, 2004.

Surfactant Therapy Affects Surfactant Therapy Affects BP, PaOBP, PaO22 & PaCO & PaCO22

•Cerebral hemodynamics (contradictory results)

–Increased

–Decreased

–Unchanged

Surfactant StudySurfactant StudyObjectivesObjectives

• 1° Objective– Determine effects on CBF– Assess whether changes in CBF are

primarily associated with changes in PaCO2 or BP

• 2° Objective– Determine the presence or absence of

cerebral autoregulation

Surfactant StudySurfactant StudyHypothesisHypothesis

Significant increases in CBF occur briefly during surfactant

administration that may be associated with brain injury in

VLBW infants

Equipment SetupEquipment Setup

CBF Velocity Measurement: CBF Velocity Measurement: Transcranial Doppler Ultrasound Transcranial Doppler Ultrasound

of the Middle Cerebral Arteryof the Middle Cerebral Artery

% Change From Baseline% Change From BaselineDuring Surfactant During Surfactant

AdministrationAdministration

CBF

PaCO2

MABP

PaO2

n=14

MABP’s Effect on the MABP’s Effect on the Cerebral VasculatureCerebral Vasculature

• Changes in MABP had much less impact on CBF than PaCO2

• In fact, a majority of infants displayed intact cerebral autoregulation--constant CBF with changes in MABP

• 2 of 14 infants had ↑CBF that was associated with ↑ MABP (impaired autoregulation)

PaCOPaCO22’s Effect on the ’s Effect on the Cerebral VasculatureCerebral Vasculature

• Changes in PaCO2 highly associated with changes in CBF in VLBW infants

• Consistent with PaCO2’s effect

CBF

CBF

The Effects of Hypercapnia on The Effects of Hypercapnia on Cerebral Autoregulation of Cerebral Autoregulation of

Ventilated VLBW InfantsVentilated VLBW Infants

Jeffrey R. Kaiser, MD, MAC. Heath Gauss, MS

D. Keith Williams, PhDIn preparation, Pediatric Research

• Permissive hypercapnia is being utilized in intubated VLBW infants to minimize ventilator-induced lung injury

• The effects of permissive hypercapnia, (PaCO2, 45-55 mm Hg), on CBF and cerebral autoregulation as well as neurologic outcome of such infants have not been primarily examined

(Mariana, et al, 1999)

Pediatrics 1999;104:1082-88

Hypercapnia and Cerebral Hypercapnia and Cerebral AutoregulationAutoregulation

• Studies in animals and adults indicate the following:– Hypercapnia is associated with impaired

autoregulation– Impaired autoregulation can be restored by

hypocapnia

Cerebral Autoregulation in Cerebral Autoregulation in Preterm InfantsPreterm Infants

0

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20 40 60 80 55

Lower Limit

Upper Limit

0

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15 25 35 45

Lower Limit

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MABP (mm Hg)

CBF (cm/s)

30 40

Hypercapnia StudyHypercapnia StudyHypothesisHypothesis

Cerebral autoregulation in VLBW infants becomes progressively impaired with increasing PaCO2

Hypercapnia StudyHypercapnia StudyObjectiveObjective

Examine the effects of increasing PaCO2 on the cerebral autoregulatory capacity of ventilated VLBW infants

Hypercapnia StudyHypercapnia StudyStatistical MethodsStatistical Methods

• The slope of the relationship between mean CBF velocity and MABP was estimated for all suctioning sessions (117, n = 43 VLBW infants)

• BP range: 30-40 mm Hg • PaCO2 was statistically fixed at 30, 35, 40, 45,

50, 55, and 60 mm Hg • Slope near 0: intact cerebral autoregulation• Slope > 0: impaired cerebral autoregulation

Hypercapnia StudyHypercapnia StudyResultsResults

(Discrete Values)(Discrete Values)

PaCO2 (mm Hg)30 35 40 45 50 55 60

Slop

e

-1.0

-0.5

0.0

0.5

1.0

Mean 95% CI

p = 0.0041

,

Effects of Increasing PaCOEffects of Increasing PaCO22 on the Relationship between on the Relationship between Mean CBF Velocity & MABPMean CBF Velocity & MABP

MABP (mm Hg)

CB

F Ve

loci

ty (c

m/s

)

30

35

40

45*50*55*60*

*Slope >0

Relationship between Highest Relationship between Highest PaCOPaCO22 in VLBW Infants in the in VLBW Infants in the

Permissive Hypercapnia Era & IVHPermissive Hypercapnia Era & IVH

• No IVH 60.8 20.4 mm Hg• Grade 1 IVH 62.2 17.4 mm Hg• Grade 2 IVH 73.7 24.4 mm Hg• Grade 3 IVH 74.2 25.6 mm Hg• Grade 4 IVH 80.6 25.3 mm Hg

P < 0.001, n = 995

Hypercapnia StudyHypercapnia Study ConclusionConclusion

• The slope of mean CBF velocity vs. MABP progressively increases with increasing PaCO2

• The cerebral circulation becomes more pressure- passive with increasing PaCO2

Hypercapnia StudyHypercapnia StudySpeculationSpeculation

These novel data describing the effects of elevated PaCO2 on the capacity for cerebral autoregulation should raise concerns regarding the liberal use of permissive hypercapnea in VLBW infants during the first week of life

AcknowledgementsAcknowledgements

• NINDS • Gerald A. Dienel, PhD• D. Keith Williams, PhD• Heath Gauss, MS• K.J.S. Anand, MBBS,

DPhil• Jeffrey M. Perlman, MD• Robert W. Arrington, MD

• Neonatologists• Carol Sikes, RN• GCRC (M01RR14288)• ACHRI, UAMS, and

CUMG Foundations• UAMS NICU Nurses &

Respiratory Therapists• Ultrasound Technicians• Parents