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The Effects of Hypercapnia on Cerebral Autoregulation and 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 cerebral autoregulation and neonatal brain injury

The Effects of Hypercapnia on Cerebral Autoregulation andNeonatal 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

neonatal perinatal definitions abbreviations
Neonatal-Perinatal Definitions & Abbreviations
  • VLBW infant: very low birth weight, birth weight ≤1500 grams (3 lbs, 5 oz)
  • Full-term infant: 37-42 wk gestation (9 months)
  • Viability: 23 wk gestation
  • IVH: intraventricular hemorrhage
  • PVL: periventricular leukomalacia
prematurity brain injury
Prematurity & Brain Injury

Sick VLBW Infant

  • 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
the magnitude of the problem of brain injury in vlbw infants
The Magnitude of the Problem of Brain Injury in VLBW Infants

Intraventricular Hemorrhage

Periventricular Leukomalacia

  • Large absolute number of VLBW infants (>55,000 per year in the U.S.)
  • High survival rates (>85%)
  • >15% of VLBW infants with severe brain injury

IVH

PVL

intact cerebral autoregulation

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IntactCerebral 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

CBF

BP

impaired cerebral autoregulation
ImpairedCerebral 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)

CBF

Lou et al, 1979

BP

changes in cbf are highly associated with changes in paco 2 in vlbw infants
Changes in CBF are Highly Associated with Changes in PaCO2 in VLBW Infants

CBF

r2 = 0.96

PaCO2

Kaiser et al, J Pediatr 2004

maximum paco 2 is associated with worst grade ivh in vlbw infants
Maximum PaCO2 is associated with Worst Grade IVH in VLBW Infants

P < 0.001, n = 574

Kaiser et al, In Submission

determination of cerebral autoregulatory capacity
Determination of Cerebral Autoregulatory Capacity
  • Instantaneous changes in CBF are compared to changes in BP after routine neonatal care procedures
  • Adult tests too invasive
experimental setup continuous measurement of cbf velocity blood gases and bp12
Experimental Setup: Continuous Measurement of CBF velocity, Blood Gases, and BP

Transcranial Doppler

Setup

experimental setup continuous measurement of cbf velocity blood gases and bp13
Experimental Setup: Continuous Measurement of CBF velocity, Blood Gases, and BP

Transcranial Doppler

Setup

Fiber Optic Sensor

experimental setup continuous measurement of cbf velocity blood gases and bp14
Experimental Setup: Continuous Measurement of CBF velocity, Blood Gases, and BP

Umbilical Arterial Catheter

Transcranial Doppler

Setup

Cardio-respiratory Monitor

Fiber Optic Sensor

how can we securely fix the doppler transducer to the newborn head for continuous monitoring
How can we securely fix the Doppler transducer to the newborn head for continuous monitoring?
vlbw infant during the study
VLBW Infant During the Study

Crocheted Hats

Courtesy of the Arkansas Homemakers Extension Service

general experimental protocol
GeneralExperimental Protocol
  • Ventilated VLBW infants during the first week of age
  • Baseline continuous monitoring of CBF, arterial blood gases, & BP (~15 min)
  • Surfactant administration or endotracheal tube suctioning
  • Monitoring ≥ 45 min
the effects of hypercapnia on cerebral autoregulation of vlbw infants hypothesis
The Effects of Hypercapnia on Cerebral Autoregulation of VLBW Infants:Hypothesis

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

  • Kaiser, Gauss, WilliamsIn Press, Pediatr Res
rationale
Rationale
  • 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 methods
Statistical 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 = 0: intact cerebral autoregulation
  • Slope > 0: impaired cerebral autoregulation
effects of increasing paco 2 on the autoregulatory plateau of vlbw infants

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)

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1

min

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Lower

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Limit

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(ml•100 gm

(ml•100 gm

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Autoregulatory Plateau

Autoregulatory Plateau

CBF

CBF

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Mean Carotid Arterial Blood Pressure

Mean Carotid Arterial Blood Pressure

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(mm Hg)

Effects of Increasing PaCO2 on the Autoregulatory Plateau of VLBW Infants

Intact

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
acknowledgements
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

Acknowledgements
proposed mechanism hypercapnia cerebral autoregulation and brain injury
Proposed Mechanism: Hypercapnia, Cerebral Autoregulation, 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
multivariate predictors of severe ivh
Multivariate Predictors of Severe IVH

*Compared to Max PaCO2 <56 mm Hg