Brain Injury in Premature Infants: The Role of Cerebral Autoregulation Jeffrey R. Kaiser, MD, MA Pediatrics, Neonatology UAMS College of Medicine Little Rock, AR Perinatal Conference February 17, 2005 Good afternoon. Today I’ll be speaking about our studies regarding the role of disturbances of cerebral autoregulation in brain injury in premature infants.

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

Prematurity & Brain Injury →→ During birth, preterm infants go from a well-controlled uterine environment into a highly stimulating & hostile one. 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 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 of 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 the Premature Infant Multifactorial Vascular: Immature thin & fragile blood vessels can easily rupture Extravascular: Poor support for the blood vessels Intravascular: Blood clotting problems Disturbed regulation of CBF & BP While the etiology of neonatal brain injury is multifactorial, including vascular, extravascular, and intravascular factors, disturbances of CBF and cerebral autoregulation play an important role, and will be discussed here.

Cerebral 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 20 40 60 80 100 120 140 Autoregulatory Plateau Lower Limit Upper Mean Carotid Arterial Blood Pressure (mm Hg) CBF (ml•100 gm - 1 min ) Intact Cerebral autoregulation is an essential physiologic mechanism that….. This process is achieved in the normal brain…

Cerebral Autoregulation in Premature 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) Although cerebral autoregulation is generally considered to be impaired in sick newborn ventilated premature infants. Recent evidence, however, suggests that many premature newborns have intact autoregulation.

Significance 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 Autoregulatory 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 In the determination of cerebral autoregulatory capacity in VLBW infants, we compared changes in CBF to changes in BP after routine neonatal care procedures. Autoregulation testing employed in adults is too invasive for use in premature infants and in fact may induce brain injury in infants lacking autoregulation Surfactant administration and endotracheal suctioning were chosen since they are commonly used procedures in ventilated VLBW infants and are known to affect BP, gas exchange, and CBF.

Experimental 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 Baseline monitoring of physiological variables begins 15 minutes before surfactant administration or endotracheal suctioning and continued for about 45 minutes post-procedure.

Surfactant Administration Acutely Affects Cerebral Hemodynamics in VLBW Infants This x-ray shows the classic “ground glass” appearance of respiratory distress syndrome, which is a condition of developmental deficiency of surfactant. Surfactant lowers alveolar surface tension, and without it, alveoli collapse. It begins to be produced in fetus between 24-28 wks. By about 35 wks gestation, most fetuses have adequate amounts of surfactant to sustain extra-uterine life. Unfortunately a majority of premature infants require mechanical ventilation due to their surfactant deficiency. Exogenous surfactant therapy began in the late 1980s and is now standard of care. This tx reduces mortality and pulmonary morbidity among premature infants. It rapidly improves pulmonary function and gas exchange, reduces pulmonary complications, such as pneumothorax, and promotes weaning from the ventilator. Kaiser JR, Gauss CH, Williams DK. Journal of Pediatrics, 2004.

Surfactant Therapy Affects BP, PaO2 & PaCO2 Cerebral hemodynamics (contradictory results) Increased Decreased Unchanged This life-saving procedure, has been associated with a number of dramatic… Unfortunately, studies examining the acute effects of surfactant on cerebral hemodynamics have produced contradictory results

Surfactant Study Objectives 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 The main objectives of this study were to use a continuous physiological monitoring system (1) to determine the acute effects of surfactant therapy on cerebral and systemic hemodynamics and gas exchange; and (2) to assess whether changes in mCBFv were predominantly associated with changes in CO2 and MABP. A secondary aim was to examine relationships among these physiological variables in order to begin to determine whether VLBW infants possess intact or impaired cerebral autoregulation

Surfactant Study Hypothesis Significant increases in CBF occur briefly during surfactant administration that may be associated with brain injury in VLBW infants We hypothesized that... especially those infants with impaired cerebral autoregulation

Equipment Setup

CBF Velocity Measurement: Transcranial Doppler Ultrasound of the Middle Cerebral Artery Continuous Doppler measurements of the middle cerebral artery CBF velocity were made using a transcranial Doppler ultrasound system. A lightweight 2 MHz transducer was placed transtemporally and secured with a crocheted hat. The system performs fast Fourier transformation analysis enabling real-time display and calculation of of the blood flow spectra and values for mean CBF velocity, as well as peak systolic and end-diastolic velocities.

% Change From Baseline During Surfactant Administration CBF MABP The data sets used in the statistical analyses were derived from the continuous raw measurements of mCBFv, PCO2, MABP, and PO2 from infants before, during, and after surfactant administration. We observed…~75% increase in CBF (Increased in every VLBW infant, Average % increase 75%) ~50% increase in carbon dioxide, Average ∆ from baseline 21 mm Hg Minimal ↑s BP: Average % increase 20 %, Average ∆ from baseline 4.5 mm Hg PaCO2 PaO2 n=14

MABP’s Effect on the Cerebral 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) MABP changes had much less impact on mCBFv than PCO2 during surfactant administration. Cerebral autoregulation was probably intact in this population since mCBFv primarily varied with PCO2 and not MABP. In contrast, 2 infants had increases in mCBFv when MABP increased and PCO2 decreased. Thus, CBF changed with MABP, suggesting a pressure-passive circulation and impaired autoregulation.

PaCO2’s Effect on the Cerebral Vasculature Changes in PaCO2 highly associated with changes in CBF in VLBW infants Consistent with PaCO2’s effect  CBF PCO2 changes were highly associated with changes in mCBFv during surfactant administration. This is consistent with PCO2‘s known effects on the cerebral vasculature, where hypercarbia produces vasodilation thus increasing CBF.  CBF

In preparation, Pediatric Research The Effects of Hypercapnia on Cerebral Autoregulation of Ventilated VLBW Infants Jeffrey R. Kaiser, MD, MA C. Heath Gauss, MS D. Keith Williams, PhD In preparation, Pediatric Research Given our observations regarding PaCO2’s influence on CBF lead us to our next series of experiments, examining “The Effects of Hypercapnia on Cerebral Autoregulation of Very Low Birth Weight Infants” We wanted to determine how current ventilatory strategies of permissive hypercapnia in the NICU affect VLBW infants capacity for cerebral autoregulation.

Pediatrics 1999;104:1082-88 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) Permissive hypercapnia is a strategy that is widely being used by neonatologists in intubated premature infants to minimize ventilator-induced lung injury. Despite its widespread use, the effects of permissive hypercapnia (PaCO2 levels 45-55 mm Hg) on CBF and in particular cerebral autoregulation, as well as neurologic outcomes of VLBW infants have not been primarily examined.

Hypercapnia and Cerebral Autoregulation Studies in animals and adults indicate the following: Hypercapnia is associated with impaired autoregulation Impaired autoregulation can be restored by hypocapnia This is despite extensive literature in animals and adults indicating that hypercapnia is associated with impaired autoregulation, and that impaired autoregulation can be restored by hyperventilation and hypocapnia. With increasing hypercapnia, there is maximal vasodilation of resistance arterioles, such that: further vasodilation becomes inadequate during hypotension. Sufficient vasoconstriction is not possible when BP increases. The cerebral circulation becomes pressure-passive.

Cerebral Autoregulation in Preterm Infants CBF (cm/s) 20 40 60 80 50 70 55 Lower Limit Upper 10 30 15 25 35 45 The BP range over which CBF remains constant is known as the autoregulatory plateau. In this portion of the curve,the slope is 0. Below and above this range, CBF changes in a pressure-passive manner. With impaired autoregulation, CBF linearly follows changes in BP. There is scant data regarding the limits of autoregulation in premature human infants, but based upon 1 study we used the narrow range of 30-40 mm Hg as the autoregulatory plateau as a conservative estimate 30 40 MABP (mm Hg)

Hypercapnia Study Hypothesis Cerebral autoregulation in VLBW infants becomes progressively impaired with increasing PaCO2 Cerebral autoregulation in VLBW infants becomes progressively impaired with increasing PaCO2 levels.

Hypercapnia Study Objective Examine the effects of increasing PaCO2 on the cerebral autoregulatory capacity of ventilated VLBW infants To examine the effects of increasing PaCO2 levels on cerebral autoregulatory capacity of ventilated VLBW infants during the first week of life.

Hypercapnia Study Statistical 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 For each suctioning session, the slope of the relationship between mCBFv and MABP was estimated over the presumed autoregulatory plateau between 30 and 40 mm Hg, when PaCO2 was statistically fixed at 30, 35, 40, 45, 50, 55, and 60 mm Hg using a multiple regression model. A slope near or equal to 0 suggests intact cerebral autoregulation. Progressive values >0 represent increasing impaired autoregulation.

Hypercapnia Study Results (Discrete Values) For PaCO2 values of 30 to 60 mm Hg, the estimated means and 95% CI of the slopes are shown here. There is a significant difference among the slopes associated with the 7 PaCO2 levels (p-value = 0.0041). Since the 95% CI for 30, 35, and 40 contained 0, these slopes were considered to represent intact autoregulation. The slopes >45 PCO2 were increasingly >0 and represent increasingly impaired autoregulation. ,

Effects of Increasing PaCO2 on the Relationship between Mean CBF Velocity & MABP The results are displayed here in a different way. Here you can see the slopes of the autoregulatory plateau with increasing PaCO2 levels. Again, the slopes for CO2 30-40 are not statistically different from 0, while the slopes for PaCO2 levels >40 progressively increase.

Relationship between Highest PaCO2 in VLBW Infants in the Permissive 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 Study Conclusion The slope of mean CBF velocity vs. MABP progressively increases with increasing PaCO2 The cerebral circulation becomes more pressure- passive with increasing PaCO2 The slope of the relationship between mCBFv and MABP increases with increasing PaCO2 levels, suggesting that the cerebral circulation becomes more pressure passive with increasing PaCO2.

Hypercapnia Study Speculation 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

Acknowledgements Neonatologists NINDS Carol Sikes, RN GCRC (M01RR14288) ACHRI, UAMS, and CUMG Foundations UAMS NICU Nurses & Respiratory Therapists Ultrasound Technicians Parents 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