Integrative Human Cardiovascular Control The Panum Institute/ Rigshospitalet, University of Copenhagen 2017 Cerebral blood flow and oxygenation, static and dynamic autoregulation, and relation to orthostatic stress Jo(Han)nes van Lieshout Academic Medical Centre, University of Amsterdam NL School of Life Sciences, University of Nottingham UK
Wieling W, Van Lieshout JJ. Clin Auton Res 2002
The fainting lark Combining the effects of a) acute arterial hypotension by gravity and b) raised intrathoracic pressure with c) cerebral vasoconstriction in response to hypocapnia
Outline of Presentation Measurement and Regulation of Cerebral Blood Flow Techniques and Methodological Issues What determines Brain Blood Flow? Static and Dynamic Cerebral Autoregulation
Cerebral Blood Flow (CBF) and Imaging Techniques Global CBF (arterial-venous diff N 2 O, 133 Xe, O 2 ) Magnetic Resonance Imaging (MRI) MRA (Magnetic Resonance Angiography & Venography) Regional CBF (Ultrasound - Transcranial Doppler) Single-Photon Emission Computed Tomography (SPECT) Positron Emission Tomography (PET) SPECT/CT and PET/CT, Near-Infrared Spectroscopy
Measurement of Global Cerebral Circulation - Inert Gas Nitrous Oxide Kety and Schmidt, J Clin Invest 1948
Fick Principle Systemic circulation: VO 2 = CO * (C a C v ) Cerebral circulation: CMRO 2 = CBF * (C a C v jug )
Ohm s Law voltage (V) = amperage (I) * resistance (R) CPP = CBF * CVR Cerebral Perfusion Pressure Cerebral Blood Flow Cerebral Vascular Resistance Applied to TransCranial Doppler Ultrasonography MAP = CBFV * CVR Mean Arterial Pressure Cerebral Blood Flow Velocity Cerebral Vascular Resistance at brain level
Transcranial Doppler Cerebral Blood Flow Velocity
Assessment of Cerebral Perfusion TCD middle cerebral artery blood velocity pro: Beat-to-beat evaluation of (regional) CBF con: larger changes in arterial distending pressure may affect MCA diameter with under/overestimation of CBF heterogeneity in cerebral vascular responsiveness
Limitations arterial pressure may not fully reflect CPP (the pressure driving CBF in the large cerebral arteries) transcranial Doppler cerebral artery velocity is taken as 'a surrogate' for CBF cerebral blood flow/velocity is the outcome measure, and a relationship to vascular control is only inferred
Reviewer s comment: Constant diameter under the conditions of the study??
Verbree et al. JAP 2014
7T MRI evaluation of Middle Cerebral Artery during Rhythmic Handgrip Exercise Sympathetic activation by handgrip exercise reduces MCA cross-sectional area 12 11 Effect of exercise on area * 2 ] 10 MCA area [mm 9 8 7 6 Male 5 Rest Handgrip Female Verbree J, Bronzwaer AS, van Buchem MA, Daemen MJAP, Van Lieshout JJ, Van Osch MJ. J Cereb Blood Flow Metab 2016
Brain vascular control during exercise Effects of exercise on cerebral metabolism are highly heterogeneous Increases in CBF are not global but localized to specific areas of the brain Lassen NA, Ingvar DH and Skinhoj E. Brain Function and Blood Flow. Sci Am. 1978;239:62-71
Limitations to be considered arterial pressure may not fully reflect the pressure driving CBF in the large cerebral arteries transcranial Doppler cerebral artery velocity is taken as 'a surrogate' for CBF cerebral blood flow/velocity is the outcome measure, and a relationship to vascular control is only inferred
Outline of Presentation Measurement and Regulation of Cerebral Blood Flow Techniques and Methodological Issues What determines Brain Blood Flow?
Which influences for brain blood flow? - brain activation (visual stimulation, exercise) - metabolic (from rest to exercise) - chemical - PaCO 2, O 2 - autoregulation - neurogenic - sympathetic system influence - endothelial cell smooth muscle cell - ATP, adenosine, brain-derived neurotrophic factor (BDNF) - cardiac output - ageing
Control of Cerebral Circulation in Health and Disease Lassen NA. Autoregulation of cerebral blood flow. Circ Res 15: 201-204, 1964
CHEMICAL (PaCO 2, PaO 2 ) 200 HYPERVENTILATION BP (mm Hg) 100 0 150 MCAV (cm s -1 ) 75 0 30 P ET CO 2 (mm Hg) 15 0 0 30 60 Time (s)
Cerebral Responsiveness to Carbon Dioxide (CO 2 reactivity of the brain) Ide K, Eliasziw M, and Poulin MJ. J Appl Physiol 95: 129-137, 2003
Activation Ingvar DH. Functional landscapes of the dominant hemisphere. Brain Res 1976
Cerebral blood flow during exercise in T2DM Activation of the brain by exercise enhances CBF
Changes in MCA V mean during exercise are similar to those recorded with the initial slope index of the 133 Xe clearance method During heavy dynamic exercise, MCA V mean increases 24 (10-47)% Jorgensen LG, Perko M, Hanel B, Schroeder TV and Secher NH. Middle Cerebral Artery Flow Velocity and Blood Flow During Exercise and Muscle Ischemia in Humans. J Appl Physiol. 1992;72:1123-1132
Effects of exercise intensity and duration on indices of cerebral blood flow and oxygenation during exercise Laughlin MH, Davis MJ, Secher NH, van Lieshout JJ, Arce-Esquivel AA, Simmons GH, Bender SB, Padilla J, Bache RJ, Merkus D and Duncker DJ. Peripheral Circulation. Compr Physiol. 2012;2:321-447.
Relationship cardiac output and MCA V from rest to exercise Reductions in Q accomplished by lower body negative pressure (LBNP), increases in Q by infusions of 25% human serum albumin Ogoh S, Brothers RM, Barnes Q, Eubank WL, Hawkins MN, Purkayastha S, Yurvati A and Raven PB. J Physiol. 2005;569:697-704.
Effects of Exercise on CBF in Heart Failure With one-legged exercise CBFV is maintained but declines with two-legged exercise Hellstrõm G, Magnusson G, Wahlgren NG, Saltin B. Physical exercise may impair cerebral perfusion in patients with chronic heart failure. Cardiol Elderly 1996
AGEING ~15% reduction in gray matter flow between the 3rd and 5th decade Shaw TG, Mortel KF, Meyer JS, Rogers RL, Hardenberg J, Cutaia MM. Cerebral blood flow changes in benign aging and cerebrovascular disease. Neurology 1984 Meyer JS, Terayama Y, Takashima S. Cerebral circulation in the elderly. Cerebrovasc Brain Metab Rev 1993
CO and CBF In heart failure: CBF substantially, but reversibly, reduced redistribution of cardiac output inadequately secures brain perfusion Gruhn N, Larsen FS, Boesgaard S, Knudsen GM, Mortensen SA, Thomsen G and Aldershvile J. Cerebral Blood Flow in Patients with Chronic Heart Failure before and after Heart Transplantation. Stroke. 2001;32:2530-2533.
BODY POSITION Bode H. Eur J Pediatr 1991 Levine BD, et al. Circulation 1994 Bondar RL, et al. Stroke 1995 Schondorf R, et al. Stroke 1997 Novak V, et al. Stroke 1998 Lipsitz LA, et al. Stroke 2000 Van Lieshout JJ, et al. Stroke 2001 Harms MPM, et al. Stroke 2000 Pott F, et al. JAP 2000 Alperin N, et al. J. Magn Reson Imaging 2005
Postural reduction in central blood volume affects the brain Assumption of the upright position carries the head above heart level BP at brain level ~ 20 mmhg Cardiac output 20-30% PCO 2 Cerebral Blood Velocity 15% Brain consumes ~20% of cardiac output
Middle cerebral artery blood velocity declines when standing 100 Standing MCA V mean (cm.s -1 ) 50 150 MAP (mmhg) 100 50 0 30 60 Time (s) Van Lieshout JJ, Pott F, Madsen PL, Van Goudoever J, Secher NH. Stroke 32: 1546-1551, 2001
Effects of Body Position on the (a-et)pco 2 gradient
Postural PETCO 2 clamping
Contribution of CO 2 on the postural restraint in cerebral perfusion spontaneous breathing isocapnic tilt Immink RV, Truijen J, Secher NH, van Lieshout JJ, J Appl Physiol 2009
Contribution of CO 2 on the postural restraint in cerebral perfusion is TRANSIENT P ET,CO2 (mmhg) 50 40 ***************************** spontaneous breathing isocapnic tilt 30 MCA V mean (cm s -1 ) 75 60 45 *** 100 MAP (mmhg) 75 50-60 0 60 120 180 240 300 Time (s) Immink RV, Truijen J, Secher NH, van Lieshout JJ, J Appl Physiol 2009
Outline of Presentation Measurement and Regulation of Cerebral Blood Flow Techniques and Methodological Issues What determines Brain Blood Flow? Static and Dynamic Cerebral Autoregulation
Dynamic Cerebal Autoregulation 130 130 Blood Pressure (%) 120 110 100 120 110 100 MCAV (%) 90 90 0 1 2 3 4 5 6 7 8 9 10 Time (s)
Effect of Dynamic Exercise on Blood Pressure What will brain blood flow do? Rasmussen P, Plomgaard P, Krogh-Madsen R, Kim YS, Van Lieshout JJ, Secher NH, Quistorff B. J Appl Physiol 2006;101:1406 Kim YS, Krogh-Madsen R, Rasmussen P, Plomgaard P, Ogoh S, Secher NH, van Lieshout JJ. Am J Physiol Heart Circ Physiol 2007;293:H467
and on Cerebral Blood Velocity autoregulation malfunction? Rasmussen P, Plomgaard P, Krogh-Madsen R, Kim YS, Van Lieshout JJ, Secher NH, Quistorff B. J Appl Physiol 2006;101:1406 Kim YS, Krogh-Madsen R, Rasmussen P, Plomgaard P, Ogoh S, Secher NH, van Lieshout JJ. Am J Physiol Heart Circ Physiol 2007;293:H467
Static and Dynamic Components of Cerebral Autoregulation (CA) Static CA reflects the overall efficiency of the system Q P Dynamic CA ability to restore cerebral blood flow within seconds in response to BP changes reflects latency of regulatory system
Cerebral Autoregulation In biological systems reflex gain is not infinite CBF CVRI Cerebral vasoconstriction Cerebral vasodilation 60 150 60 150 Perfusion Pressure mmhg Perfusion Pressure mmhg Courtesy of Eubank and Raven
Dynamic Cerebral Autoregulation - Assessment Inducing a fall in mean arterial pressure (cuff release; Aaslid manoeuvre) Rest and steady-state orthostatic stress Spontaneous and induced oscillations
Cerebrovascular autoregulation Roy CS and Sherrington CS. J Physiol. 1890;11:85-108. Panerai RB. Physiol Meas. 1998;19:305-338. Lassen NA. Circ Res. 1964;15:201-204. Harper AM.. JNeurolNeurosurgPsychiatry. 1966;29:398-403. Strandgaard S, MacKenzie ET, Sengupta D, Rowan JO, Lassen NA and Harper AM. CircRes. 1974;34:435-440. Aaslid R, Lindegaard KF, Sorteberg W and Nornes H. Stroke. 1989;20:45-52. Ritz K, Denswil NP, Stam OC, van Lieshout JJ and Daemen MJ. Circulation. 2014;130:1407-14.
Cerebrovascular adaptation following release of muscle ischemia Aaslid R, Lindegaard KF, Sorteberg W, Nornes H. Stroke 1989; 20(1):45-52. Lind-Holst, Cotter JDm Helge JW, Boushel R, Augustesen H, Van Lieshout JJ, Pott FC. J Appl Physiol 2011
Transfer of Spontaneous Oscillations in Blood Pressure to Cerebral Blood Velocity 130 130 Blood Pressure (%) 120 110 100 120 110 100 MCAV (%) 90 0 1 2 3 4 5 6 7 8 9 10 Time (s) 90 ABP to CBFV transfer described in terms of phase and gain
Dynamic Cerebral Autoregulation - Phase Difference CBFV BP
Dynamic Cerebral Autoregulation - Gain CBFV BP
Normal Dynamic Cerebral Autoregulation = MCA V mean = MAP brain 0.067 Hz Phase 50, Gain 0.33 0.100 Hz Phase 119, Gain 0.53 0.167 Hz Phase 77, Gain 0.33
chemical - PaCO 2, O 2 activation: visual stimulation, exercise ageing body position autoregulation cardiac output neurogenic - sympathetic system influence NEUROGENIC SYMPATHETIC INFLUENCE
Sympathetic effects on CBF during exercise role of sympathetic activation for CBF controversial dense sympathetic innervation middle size brain arteries sympathetic innervation of larger cerebral arteries NE spillover from brain vasculature in healthy humans but not in patients with autonomic failure sympathetic activation reduces MCA cross-sectional area Mitchell DA, Lambert G, Secher NH, Raven PB, van Lieshout JJ and Esler MD. Jugular Venous Overflow of Noradrenaline from the Brain: A Neurochemical Indicator of Cerebrovascular Sympathetic Nerve Activity in Humans. J Physiol. 2009;587:2589-97. Strandgaard S and Sigurdsson ST. Counterpoint: Sympathetic Nerve Activity Does Not Influence Cerebral Blood Flow. J Appl Physiol. 2008;105:1366-1367. Van Lieshout JJ and Secher NH. Point: Counterpoint: Sympathetic Activity Does Cerebral Blood Flow. Journal of Applied Physiology. 2008;105:1364-1366. Verbree J, Bronzwaer AS, van Buchem MA, Daemen MJAP, Van Lieshout JJ, Van Osch MJ. J Cereb Blood Flow Metab 2016
Control of Cerebral Circulation in Health and Disease Lassen NA. Autoregulation of cerebral blood flow. Circ Res 15: 201-204, 1964
Coupling of synaptic activity with substrate utilization (neurovascular coupling) LACTATE Roy CS and Sherrington CS. J Physiol. 1890;11:85-108. Magistretti PJ and Pellerin L. News Physiol Sci. 1999 Pellerin L and Magistretti PJ. J CerebB lood Flow Metab. 2003 Quistorff B, Secher NH, Van Lieshout JJ. FASEB J 2008 Van Hall G, Stromstad M, Rasmussen P, Jans O, Zaar M, Gam C, Quistorff B, Secher NH, Nielsen HB. J Cereb Blood Flow Metab 2009
Summing up... Postural decline in cerebral perfusion/oxygenation not explained by CO 2 - no infinite gain in CA capacity Influence of cardiac output on cerebral perfusion independent from arterial pressure CBF measurement techniques have limitations Heterogeneity in cerebral vascular responsiveness and probably in dynamic autoregulatory capacity
Dynamic Cerebal Autoregulation 130 130 Blood Pressure (%) 120 110 100 120 110 100 MCAV (%) 90 90 0 1 2 3 4 5 6 7 8 9 10 Time (s)
ischemic s-1) (cm non-ischemic s-1) (cm Pressure Blood (mmhg) Cerebral Autoregulation in Acute Ischemic Stroke (MCA Territory) 150 100 50 100 50 Blood Pressure (%) 130 120 110 100 90 0 1 2 3 4 5 6 7 8 9 10 130 120 110 100 90 MCAV (%) Time (s) 0 100 50 0 0 15 30 45 60 Time (s) Immink RV, Van Montfrans GA, Stam J, Karemaker JM, Diamant M, Van Lieshout JJ. Stroke 36: 2595-2600, 2005
Dynamic Cerebral Autoregulation in Uncomplicated Type 2 Diabetes Mellitus Kim YS, Immink RV, Stok WJ, Karemaker JM, Secher NH, van Lieshout JJ. Clin Sci (Lond) 115: 255-262, 2008
Static Cerebral Autoregulation in Type 2 Diabetes during intensive blood pressure control Kim YS, Davis SC, Truijen J, Stok WJ, Secher NH, van Lieshout JJ. Hypertension 2011;57(4):738-45.
Benefit for patients?
Static and Dynamic CA
Outline of Presentation Measurement and Regulation of Cerebral Blood Flow Techniques and Methodological Issues
Heart-brain axis Cc cc Competition brain vs. working muscles
The brain activates the muscles, but the muscles represent a potent competitor for continuous provision of oxygen and substrate upon which the brain relies
Brain vs. Skeletal Muscle The brain is active under all living conditions Postural change affects brain blood flow Brain vascular bed is small, strongly regulated by cerebral autoregulation and the partial pressure of arterial carbon dioxide (PaCO2) Brain ~ 2% of total body mass but ~20% whole-body oxygen consumption at rest Brain function deteriorates if oxygenation > 10%
Cerebral Tissue Oxygenation - Near Infra-Red Spectroscopy (NIRS) Analog channels Light sources 905 Fiber-optic cables 850 770 Detector
Assessment of Cerebral Oxygenation Near-InfraRed Spectroscopy cerebral oxygenation pro: NIRS follows changes in cerebral oxygenation in parallel with CBF as determined by 133 Xe NIRS tracks brain capillary oxygen saturation (halfway arterial and jugular venous O 2 ) for SvO 2 40 80 % and CBFV 29 65 cm/s con: hemoglobin is contained in arterioles, capillaries, and venules, but the relative position of pigments determined by NIRS is unknown Rostrup E, Law I, Pott FC, Ide K, Knudsen GM. Brain Res 2002;954(2):183-93. Villringer K, Minoshima S, Hock C, Obrig H, Ziegler S, Dirnagl U, Schwaiger M, Villringer A. Adv Exp Med Biol 1997;413:149-53. Rasmussen P, Dawson EA, Nybo L, Van Lieshout JJ, Secher NH, Gjedde A. J Cereb Blood Flow Metab 2007 May;27(5):1082-93.
Cerebral Circulation Transcranial Doppler Blood Flow Velocity & NIRS Cortical oxygenation 6 50 chbo 2 (mmol/l) 5 4 3 2 1 0 40 30 20 10 0 V mean (%) -1-10 0 10 20 30 40 Time (s)
Saturation recording of the brain during cardiopulmonary bypass. (CPB) 5/29/2017 79
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Ono M, Brady K, Easley RB, et al. Duration and magnitude of blood pressure below cerebral autoregulation threshold during cardiopulmonary bypass is associated with major morbidity and operative mortality. The Journal of thoracic and cardiovascular surgery. 2014;147(1):10.1016/j.jtcvs.2013.07.069. doi:10.1016/j.jtcvs.2013.07.069. 5/29/2017 81
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Reduced Dynamic Cerebral Autoregulatory Efficacy in Uncomplicated T2DM 5/29/2017
Reduced Dynamic Cerebral Autoregulatory Efficacy in Uncomplicated T2DM 5/29/2017
Determination of delay between BP and CBFv BP CBFv 5/29/2017 86
Time domain analysis Correlation between MAP and MCAv mean Find maximal correlation Phase (time domain, in seconds) Gain 5/29/2017 87
Correlation 5/29/2017 88
Cerebral Autoregulation during Anesthesia 5/29/2017 89
Back to degrees/radians Claude Julien; The enigma of Mayer waves: Facts and models. Cardiovasc Res 2006; 70 (1): 12-21. doi: 10.1016/j.cardiores.2005.11.008 5/29/2017 90
Previously, now and later
Future Pre-assessment prior to anesthesia Measuring cerebral blood flow and at least Blood pressure CO 2 Extract models describing the relation between arterial blood pressure and cerebral blood flow Intra-operative application of cerebral blood flow model as developed during pre-assessment 5/29/2017 92
Summarized Machine learning: Requires blood pressure and CO 2 ARX model Requires blood pressure and CO 2 xdca Requires blood pressure and brain perfusion monitoring with TCD or NIRS Disregards CO 2 contribution 5/29/2017 93
Concluding remarks Modeling of CBFv from BP and CO 2 feasible Machine Learning method has constant offset ARX model, faster but less consistent Ideally: Build general model instead of pre -> intra anesthesia per subject 5/29/2017 94