The Effects of The Effects of Hypercapnia on Cerebral Hypercapnia on Cerebral Autoregulation and Autoregulation and Neonatal Brain Injury Neonatal Brain Injury Jeffrey R. Kaiser, MD, MA Department of Pediatrics, Section of Neonatology UAMS College of Medicine Maternal Fetal Network Meeting October 7, 2005 Supported by NINDS 1 K23 NS43185
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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 55,000 per year in the U.S.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
Worst Grade Max PaCO2
(mm Hg)
95% CI
0 66 64-68
1 68 63-73
2 76 69-84
3 78 71-84
4 81 72-91
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•1
00
gm
–1m
in–1
)
0
10
20
30
40
50
60
70
20 40 60 80 100Systolic Blood Pressure (mm Hg)
CB
F (m
l•1
00
gm
–1m
in–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
Factor OR 95% CI P value
Gestational age (w) .81 .71-.93 .003
Apgar 1 min >3 .64 .39-1.1 NS
Multiples 1.8 1.0-3.2 .035
Vasopressors 2.0 1.1-3.4 .019
Max PaCO2 56-63* 3.1 1.1-8.9 .037
Max PaCO2 63-75* 3.9 1.4-11.1 .009
Max PaCO2 >75* 4.7 1.7-12.8 .003*Compared to Max PaCO2 <56 mm Hg
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