1. 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

2. Neonatal-Perinatal Definitions & 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

3. Prematurity & 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

4. The Magnitude of the Problem of Brain Injury in VLBW Infants >55,000 per year in the U.S.Large absolute number of VLBW infants (>55,000 per year in the U.S.) >85%High survival rates (>85%) >15%>15% of VLBW infants with severe brain injury Intraventricular Hemorrhage Periventricular Leukomalacia IVH PVL

5. Intact Cerebral 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 20406080100 Plateau Lower Limit Upper Limit 0 20 40 60 80 100 120 140 20406080100 Lower Limit Upper Limit BP CBF

6. Impaired Cerebral 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 BP Lou et al, 1979

7. PaCO 2 is a Potent Regulator of Cerebral Arterioles and CBF  CBF  CBF

8. Changes in CBF are Highly Associated with Changes in PaCO 2 in VLBW Infants CBF PaCO 2 Kaiser et al, J Pediatr 2004 r 2 = 0.96

9. Maximum PaCO 2 is associated with Worst Grade IVH in VLBW Infants Worst GradeMax PaCO 2 (mm Hg) 95% CI 06664-68 16863-73 27669-84 37871-84 48172-91 P < 0.001, n = 574Kaiser et al, In Submission

10. Determination of Cerebral Autoregulatory Capacity Instantaneous changes in CBF are compared to changes in BP after routine neonatal care procedures Adult tests too invasive

11. Experimental Setup: Continuous Measurement of CBF velocity, Blood Gases, and BP Setup

12. Experimental Setup: Continuous Measurement of CBF velocity, Blood Gases, and BP Transcranial Doppler Setup

13. Experimental Setup: Continuous Measurement of CBF velocity, Blood Gases, and BP Transcranial Doppler Fiber Optic Sensor Setup

14. Experimental Setup: Continuous Measurement of CBF velocity, Blood Gases, and BP Transcranial Doppler Fiber Optic Sensor Setup Umbilical Arterial Catheter Cardio-respiratory Monitor

15. How can we securely fix the Doppler transducer to the newborn head for continuous monitoring?

16. First we used tape…

17. VLBW Infant During the Study Courtesy of the Arkansas Homemakers Extension Service Crocheted Hats

18. General Experimental Protocol Ventilated VLBW infants during the first week of age continuousBaseline continuous monitoring of CBF, arterial blood gases, & BP (~15 min) Surfactant administration or endotracheal tube suctioning Monitoring ≥ 45 min

19. The Effects of Hypercapnia on Cerebral Autoregulation of VLBW Infants: Hypothesis Cerebral autoregulation becomes progressively impaired with increasing PaCO 2 in ventilated VLBW infants during the first week of age Pediatr Res –Kaiser, Gauss, Williams In Press, Pediatr Res

20. Rationale Permissive hypercapnia (PaCO 2 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

21. Statistical Methods The slope of the relationship between CBF and BP was estimated for 43 VLBW infants during suctioning sessions (n = 117) PaCO 2 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

22. Effects of Increasing PaCO 2 on the Autoregulatory Plateau of VLBW Infants 0 20 40 60 80 100 120 140 20406080100 Autoregulatory Plateau Lower Limit Upper Limit Mean Carotid Arterial Blood Pressure(mm Hg) CBF (ml100 gm – 1 min – 1 ) 0 20 40 60 80 100 120 140 20406080100 Autoregulatory Plateau Lower Limit Upper Limit Mean Carotid Arterial Blood Pressure(mm Hg) CBF (ml100 gm – 1 min – 1 ) Intact

23. Effects of Increasing PaCO 2 on the Autoregulatory Plateau of VLBW Infants Impaired

24. Conclusions and Speculation The slope of the relationship between CBF vs. BP increases with increasing PaCO 2 The cerebral circulation becomes progressively pressure passive with increasing PaCO 2 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

25. 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

26. VLBW Infants →

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28. Thank You

29. 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

30. Maximum PaCO 2 Distribution

31. Multivariate Predictors of Severe IVH FactorOR95% CIP value Gestational age (w).81.71-.93.003 Apgar 1 min >3.64.39-1.1NS Multiples1.81.0-3.2.035 Vasopressors2.01.1-3.4.019 Max PaCO 2 56-63*3.11.1-8.9.037 Max PaCO 2 63-75*3.91.4-11.1.009 Max PaCO 2 >75*4.71.7-12.8.003 *Compared to Max PaCO 2 <56 mm Hg