The Effects of Hypercapnia on Cerebral Autoregulation and Neonatal Brain Injury

1. 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

2. 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

3. 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

4. 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

5. 140 140 120 120 Upper Upper Lower Lower 100 100 Limit Limit Limit Limit 80 80 60 60 40 40 20 20 Plateau 0 0 20 20 40 40 60 60 80 80 100 100 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

6. 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

7. PaCO2 is a Potent Regulator of Cerebral Arterioles and CBF  CBF  CBF

8. Changes in CBF are Highly Associated with Changes in PaCO2 in VLBW Infants CBF r2 = 0.96 PaCO2 Kaiser et al, J Pediatr 2004

9. Maximum PaCO2 is associated with Worst Grade IVH in VLBW Infants P < 0.001, n = 574 Kaiser 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 Setup Fiber Optic Sensor

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

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 Crocheted Hats Courtesy of the Arkansas Homemakers Extension Service

18. 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

19. 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

20. 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

21. 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

22. 140 140 ) ) 120 120 1 1 – – min min Upper Upper Lower Lower 100 100 Limit Limit Limit Limit 1 1 – – 80 80 (ml•100 gm (ml•100 gm 60 60 40 40 Autoregulatory Plateau Autoregulatory Plateau CBF CBF 20 20 0 0 20 20 40 40 60 60 80 80 100 100 Mean Carotid Arterial Blood Pressure Mean Carotid Arterial Blood Pressure (mm Hg) (mm Hg) Effects of Increasing PaCO2 on the Autoregulatory Plateau of VLBW Infants Intact

23. Effects of Increasing PaCO2 on the Autoregulatory Plateau of VLBW Infants Impaired

24. 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

25. 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

26. VLBW Infants →

27. VLBW Infants →

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 PaCO2Distribution

31. Multivariate Predictors of Severe IVH *Compared to Max PaCO2 <56 mm Hg