6 The Effects Of Hypercapnia On Cerebral Autoregulation And Neonatal Brain Injury

The Effects of Hypercapnia on The Effects of Hypercapnia on Cerebral Autoregulation andCerebral Autoregulation and

Neonatal Brain InjuryNeonatal Brain Injury

Jeffrey R. Kaiser, MD, MADepartment of Pediatrics, Section of Neonatology

UAMS College of MedicineMaternal Fetal Network Meeting

October 7, 2005

Supported byNINDS

1 K23 NS43185

Neonatal-Perinatal Neonatal-Perinatal Definitions & AbbreviationsDefinitions & Abbreviations

• VLBW infantVLBW infant: very low birth weight, birth weight ≤1500 grams (3 lbs, 5 oz)

• Full-term infantFull-term infant: 37-42 wk gestation (9 months)

• ViabilityViability: ∼23 wk gestation

• IVHIVH: intraventricular hemorrhage

• PVLPVL: periventricular leukomalacia

Prematurity & Brain InjuryPrematurity & Brain Injury

• Advances in obstetrics & newborn intensive care have led to dramatic improvements in survival

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

• While causes of neonatal brain injury are multifactorial, our research focuses on disturbances of CBF regulation

Sick VLBW Infant

The Magnitude of the The Magnitude of the Problem of Brain Injury in Problem of Brain Injury in

VLBW InfantsVLBW Infants

• Large absolute number of VLBW infants (>>55,000 per year in the U.S.55,000 per year in the U.S.)

• High survival rates (>>85%85%)• >15%>15% of VLBW infants with severe brain injury

Intraventricular Hemorrhage Periventricular Leukomalacia

IVH PVL

IntactIntactCerebral AutoregulationCerebral Autoregulation

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

• Constriction or relaxation of terminal cerebral arterioles

• Autoregulatory plateau has slope 0

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

0

20

40

60

80

100

120

140

20 40 60 80 100

Plateau

Lower

Limit

Upper

Limit

0

20

40

60

80

100

120

140

20 40 60 80 100

Lower

Limit

Upper

Limit

BPBP

CBFCBF

ImpairedImpairedCerebral AutoregulationCerebral Autoregulation

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

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

• VLBW infants with impaired autoregulation more commonly develop IVH (Milligan 1980, Pryds 1989, Tsuji 2002)

CBFCBF

BPBP

Lou et al, 1979

PaCOPaCO22 is a Potent Regulator is a Potent Regulator

of Cerebral Arterioles and of Cerebral Arterioles and CBFCBF

↓ CBF

↑ CBF

Changes in CBF are Highly Changes in CBF are Highly Associated with Changes in Associated with Changes in

PaCOPaCO22 in VLBW Infants in VLBW Infants

CBFCBF

PaCOPaCO22

Kaiser et al, J Pediatr 2004

r2 = 0.96

Maximum PaCOMaximum PaCO22 is is associated with Worst associated with Worst

Grade IVH in VLBW InfantsGrade IVH in VLBW Infants

72-91814

71-84783

69-84762

63-73681

64-68660

95% CIMax PaCO2

(mm Hg)

Worst Grade

P < 0.001, n = 574 Kaiser et al, In Submission

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

Experimental Setup: Experimental Setup: Continuous Continuous Measurement of CBF velocity, Measurement of CBF velocity,

Blood Gases, and BPBlood Gases, and BP

Setup

Experimental Setup:Experimental Setup: Continuous Continuous Measurement of CBF velocity, Measurement of CBF velocity,

Blood Gases, and BPBlood Gases, and BP

Transcranial Doppler

Setup

Experimental Setup: Continuous Experimental Setup: Continuous Measurement of CBF velocity,Measurement of CBF velocity,

Blood Gases, Blood Gases, and BPand BP

Transcranial Doppler

Fiber Optic Sensor

Setup

Experimental Setup: Continuous Experimental Setup: Continuous Measurement of CBF velocity, Measurement of CBF velocity,

Blood Gases, andBlood Gases, and BP BP

Transcranial Doppler

Fiber Optic Sensor

Setup

Umbilical Arterial Catheter

Cardio-respiratory Monitor

How can we securely fix the Doppler transducer to the newborn head for

continuous monitoring?

First we used tape…First we used tape…

VLBW Infant During the Study

Courtesy of the Arkansas Homemakers Extension Service

Crocheted Hats

GeneralGeneralExperimental ProtocolExperimental Protocol

• Ventilated VLBW infants during the first week of age

• Baseline continuouscontinuous monitoring of CBF, arterial blood gases, & BP (~15 min)

• Surfactant administration or endotracheal tube suctioning

• Monitoring ≥ 45 min

The Effects of Hypercapnia on Cerebral The Effects of Hypercapnia on Cerebral Autoregulation of VLBW Infants:Autoregulation of VLBW Infants:

HypothesisHypothesis

Cerebral autoregulation becomes progressively impaired with increasing PaCO2 in ventilated VLBW infants during the first week of age

– Kaiser, Gauss, Williams In Press, Pediatr ResPediatr Res

RationaleRationale

• Permissive hypercapnia (PaCO2 45-55 mm Hg) is a ventilatory strategy used by neonatologists to minimize lung damage in VLBW infants

• The problem:– If hypercapnia is associated with impaired cerebral

autoregulation– and impaired cerebral autoregulation is associated

with brain injury

• Then there are thousands of VLBW infants per year at risk for brain injury

Statistical MethodsStatistical Methods

• The slope of the relationship between CBF and BP was estimated for 43 VLBW infants during suctioning sessions (n = 117)

• PaCO2 was statistically fixed at 30, 35, 40, 45, 50, 55, and 60 mm Hg

• Slope = 0Slope = 0: intact cerebral autoregulation• Slope > 0Slope > 0: impaired cerebral autoregulation

Effects of Increasing PaCOEffects of Increasing PaCO22 on the Autoregulatory Plateau on the Autoregulatory Plateau

of VLBW Infantsof VLBW Infants

MABP (mm Hg)

CB

F V

elo

city

(cm

/s)

30

35

40

45*

50*

55*60*

*Slope >0

0

20

40

60

80

100

120

140

20 40 60 80 100

Autoregulatory Plateau

Lower Limit

Upper Limit

Mean Carotid Arterial Blood Pressure (mm Hg)

CB

F (

ml•

100

gm–1

min

–1 )

0

20

40

60

80

100

120

140

20 40 60 80 100

Autoregulatory Plateau

Lower Limit

Upper Limit

Mean Carotid Arterial Blood Pressure (mm Hg)

CB

F (

ml•

100

gm–1

min

–1 ) Intact

Effects of Increasing PaCOEffects of Increasing PaCO22 on the Autoregulatory Plateau on the Autoregulatory Plateau

of VLBW Infantsof VLBW Infants

MABP (mm Hg)

CB

F V

elo

city

(cm

/s)

30

35

40

45*

50*

55*60*

*Slope >0

0

10

20

30

40

50

60

70

20 40 60 80 100Systolic Blood Pressure (mm Hg)

CB

F (m

l•10

0 g

m–1

min

–1)

0

10

20

30

40

50

60

70

20 40 60 80 100Systolic Blood Pressure (mm Hg)

CB

F (m

l•10

0 g

m–1

min

–1) Impaired

Conclusions and Speculation Conclusions and Speculation

• The slope of the relationship between CBF vs. BP increases with increasing PaCO2

• The cerebral circulation becomes progressively pressure passive with increasing PaCO2

• We speculate that the continued use of permissive hypercapnia during the early neonatal period in VLBW infants may be associated with brain injury, and its use should be reconsidered

AcknowledgementsAcknowledgements

• NINDS• Gerald A. Dienel, PhD• Jeffrey M. Perlman, MD• D. Keith Williams, PhD• K.J.S. Anand, MBBS,

DPhil• UAMS Neonatologists• Carol Sikes, RN

• C. Heath Gauss• Melanie Mason, RN• GCRC (M01RR14288)• UAMS NICU Nurses &

Respiratory Therapists• UAMS Ultrasound

Technicians• Parents

VLBW InfantsVLBW Infants

→

VLBW InfantsVLBW Infants

→

Thank YouThank You

Proposed Mechanism: Proposed Mechanism: Hypercapnia, Cerebral Hypercapnia, Cerebral

Autoregulation, and Brain InjuryAutoregulation, and Brain Injury

• With increasing hypercapnia there is maximal vasodilation of cerebral resistance arterioles– Additional vasodilation is inadequate if BP falls

– Sufficient vasoconstriction is not possible if BP increases

– CBF becomes pressure-passive

– Ischemia/reperfusion →→IVH

Maximum PaCOMaximum PaCO22

DistributionDistribution

PaCO2 (mm Hg)

30 40 50 60 70 80 90 100 110 120 130 140

Co

un

t

0

20

40

60

80

10056 63 75

Q1 Q2 Q3 Q4

Multivariate Predictors of Multivariate Predictors of Severe IVHSevere IVH

.0031.7-12.84.7Max PaCO2 >75*

.0091.4-11.13.9Max PaCO2 63-75*

.0371.1-8.93.1Max PaCO2 56-63*

.0191.1-3.42.0Vasopressors

.0351.0-3.21.8Multiples

NS.39-1.1.64Apgar 1 min >3

.003.71-.93.81Gestational age (w)

P value95% CIORFactor

*Compared to Max PaCO2 <56 mm Hg