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Scientific References

Magnetic Resonance Imaging–Based Cerebrovascular Reactivity and Hemodynamic Reserve: A Review of Method Optimization and Data Interpretation

Joseph A. Fisher, Lashmi Venkatraghavan and David J. Mikulis. Stroke. 2018;49:2011–2018.
Physiological Control of Cerebral Blood Flow
Given adequate perfusion pressure and nonlimiting intracranial or venous pressure, cerebral blood flow (CBF) is regulated to match cerebral metabolic rate of oxygen (CMRO2). Variations in perfusion pressure are addressed by adjusting downstream vascular resistance, termed autoregulation.

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Non-invasive Prospective Targeting of Arterial P(CO2) in Subjects at Rest

Shoji Ito, Alexandra Mardimae, Jay Han, James Duffin, Greg Wells, Ludwik Fedorko, Leonid Minkovich, Rita Katznelson, Massimiliano Meineri, Tamara Arenovich, Cathie Kessler, Joseph A Fisher. J Physiol. 2008 Aug 1;586(15):3675-82. doi: 10.1113/jphysiol.2008.154716. Epub 2008 Jun 19.
Accurate measurements of arterial P(CO2) (P(a,CO2)) currently require blood sampling because the end-tidal P(CO2) (P(ET,CO2)) of the expired gas often does not accurately reflect the mean alveolar P(CO2) and P(a,CO2). Differences between P(ET,CO2) and P(a,CO2) result from regional inhomogeneities in perfusion and gas exchange.

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Effects of Carbonic Anhydrase Inhibition on Ventilation-perfusion Matching in the Dog Lung

E R Swenson, H T Robertson, M P Hlastala. J Clin Invest. 1993 Aug;92(2):702-9. doi: 10.1172/JCI116640.
Lung carbonic anhydrase (CA) permits rapid pH responses when changes in regional ventilation or perfusion alter airway and alveolar PCO2. These pH changes affect airway and vascular resistances and lung compliance to optimize the balance of regional ventilation (VA) and perfusion (Q) in the lung. To test the hypothesis that these or other CA-dependent mechanisms contribute to VA/Q matching, we administered acetazolamide (25 mg/kg intravenously) to six anesthetized and paralyzed dogs and measured VA/Q relationships before and after CA inhibition by the multiple inert gas elimination technique.

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Carbon Dioxide added late in Inspiration Reduces Ventilation-perfusion Heterogeneity without causing Respiratory Acidosis

Thomas V Brogan, H Thomas Robertson, Wayne J E Lamm, Jennifer E Souders, Erik R Swenson. J Appl Physiol (1985). 2004 May;96(5):1894-8. doi: 10.1152/japplphysiol.00160.2003. Epub 2003 Dec 5.
We have shown previously that inspired CO2 (3-5%) improves ventilation-perfusion (Va/Q) matching but with the consequence of mild arterial hypercapnia and respiratory acidosis. We hypothesized that adding CO2 only late in inspiration to limit its effects to the conducting airways would enhance Va/Q matching and improve oxygenation without arterial hypercapnia. CO2 was added in the latter half of inspiration in a volume aimed to reach a concentration of 5% in the conducting airways throughout the respiratory cycle.

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End-inspiratory Rebreathing Reduces the End-tidal to Arterial PCO2 Gradient in Mechanically Ventilated Pigs

Jorn Fierstra, Matthew Machina, Anne Battisti-Charbonney, James Duffin, Joseph Arnold Fisher, Leonid Minkovich. Intensive Care Med. 2011 Sep;37(9):1543-50. doi: 10.1007/s00134-011-2260-y. Epub 2011 Jun 7.
Purpose: Noninvasive monitoring of the arterial partial pressures of CO2 (PaCO2) of critically ill patients by measuring their end-tidal partial pressures of CO2 (PETCO2) would be of great clinical value. However, the gradient between PETCO2 and PaCO2 (PET-aCO2) in such patients typically varies over a wide range. A reduction of the PET-aCO2 gradient can be achieved in spontaneously breathing healthy humans using an end-inspiratory rebreathing technique.

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Non-invasive Accurate Measurement of Arterial PCO2 in a Pediatric Animal Model

Jorn Fierstra, Jeff D Winter, Matthew Machina, Jelena Lukovic, James Duffin, Andrea Kassner, Joseph A Fisher. J Clin Monit Comput. 2013 Apr;27(2):147-55. doi: 10.1007/s10877-012-9403-8. Epub 2012 Oct 26.
The PCO2 in arterial blood (PaCO2) is a good parameter for monitoring ventilation and acid-base changes in ventilated patients, but its measurement is invasive and difficult to obtain in small children. Attempts have been made to use the partial pressure of CO2 in end-tidal gas (PETCO2), as a noninvasive surrogate for PaCO2. Studies have revealed that, unfortunately, the differences between PETCO2 and PaCO2 are too variable to be clinically useful.

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Sequential Gas Delivery Provides Precise Control of Alveolar Gas Exchange

Fisher JA, Iscoe S, Duffin J. Respiratory Physiology & Neurobiology, 31 Jan 2016, 225:60-69 doi: 10.1016/j.resp.2016.01.004
Of the factors determining blood gases, only alveolar ventilation (VA) is amenable to manipulation. However, current physiology text books neither describe how breath-by-breath VA can be measured, nor how it can be precisely controlled in spontaneously breathing subjects. And such control must be effected independent of minute ventilation (VE) and the pattern of breathing. Control of VA requires the deliberate partition of inhaled gas between the alveoli and the anatomical deadspace.

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Neuroimaging Assessment of Cerebrovascular Reactivity in Concussion: Current Concepts, Methodological Considerations, and Review of the Literature

Michael J. Ellis, Lawrence N. Ryner, Olivia Sobczyk,10 Jorn Fierstra, David J. Mikulis, Joseph A. Fisher, James Duffin and W. Alan C. Mutch. Front Neurol. 2016; 7: 61. Published online 2016 Apr 29. doi: 10.3389/fneur.2016.00061
Concussion is a form of traumatic brain injury (TBI) that presents with a wide spectrum of subjective symptoms and few objective clinical findings. Emerging research suggests that one of the processes that may contribute to concussion pathophysiology is dysregulation of cerebral blood flow (CBF) leading to a mismatch between CBF delivery and the metabolic needs of the injured brain. Cerebrovascular reactivity (CVR) is defined as the change in CBF in response to a measured vasoactive stimulus.

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The CO2 Stimulus for Cerebrovascular Reactivity: Fixing Inspired Concentrations vs. Targeting End-tidal Partial Pressures

Joseph A Fisher. J Cereb Blood Flow Metab. 2016 Jun;36(6):1004-11. doi: 10.1177/0271678X16639326. Epub 2016 Mar 21.
Cerebrovascular reactivity (CVR) studies have elucidated the physiology and pathophysiology of cerebral blood flow regulation. A non-invasive, high spatial resolution approach uses carbon dioxide (CO2) as the vasoactive stimulus and magnetic resonance techniques to estimate the cerebral blood flow response. CVR is assessed as the ratio response change to stimulus change. Precise control of the stimulus is sought to minimize CVR variability between tests, and show functional differences.

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Non-invasive Measurement of Cardiac Output Using an Iterative, Respiration-based Method

M Klein, L Minkovich, M Machina, M Selzner, V N Spetzler, J M Knaak, D Roy, J Duffin, J A Fisher. Br J Anaesth. 2015 Mar;114(3):406-13. doi: 10.1093/bja/aeu377. Epub 2014 Dec 8.
Background: Current non-invasive respiratory-based methods of measuring cardiac output [Formula: see text] make doubtful assumptions and encounter significant technical difficulties. We present a new method using an iterative approach [Formula: see text], which overcomes limitations of previous methods.

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Assessment of Myocardial Reactivity to Controlled Hypercapnia with Free-breathing T2-prepared Cardiac Blood Oxygen Level–Dependent MR Imaging

Hsin-Jung Yang, Roya Yumul, Richard Tang, Ivan Cokic, Michael Klein, Avinash Kali, Olivia Sobczyk, Behzad Sharif, Jun Tang, Xiaoming Bi, Sotirios A. Tsaftaris, Debiao Li, Antonio Hernandez Conte, Joseph A. Fisher, Rohan Dharmakumar.
Cardiac stress testing is the standard of care for diagnosing ischemic heart disease (1). It is performed in nearly 10 million patients each year in the United States alone. It is conventionally initiated with exercise to induce hyperemia, and it is coupled with imaging to identify stress-induced failure to increase perfusion, or frank hypoperfusion in myocardial territories.

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Measuring Cerebrovascular Reactivity: the Dynamic Response to a Step Hypercapnic Stimulus

Julien Poublanc, Adrian P Crawley, Olivia Sobczyk, Gaspard Montandon, Kevin Sam, Daniel M Mandell, Paul Dufort, Lashmikumar Venkatraghavan, James Duffin, David J Mikulis, Joseph A Fisher. J Cereb Blood Flow Metab. 2015 Nov;35(11):1746-56. doi: 10.1038/jcbfm.2015.114. Epub 2015 Jul 1.
We define cerebral vascular reactivity (CVR) as the ratio of the change in blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) signal (S) to an increase in blood partial pressure of CO2 (PCO2): % Δ S/Δ PCO2 mm Hg. Our aim was to further characterize CVR into dynamic and static components and then study 46 healthy subjects collated into a reference atlas and 20 patients with unilateral carotid artery stenosis. We applied an abrupt boxcar change in PCO2 and monitored S.

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A Conceptual Model for CO2-induced Redistribution of Cerebral Blood Flow with Experimental Confirmation using BOLD MRI

O Sobczyk, A Battisti-Charbonney, J Fierstra, D M Mandell, J Poublanc, A P Crawley, D J Mikulis, J Duffin, J A Fisher. Neuroimage. 2014 May 15;92:56-68. doi: 10.1016/j.neuroimage.2014.01.051. Epub 2014 Feb 5.
Cerebrovascular reactivity (CVR) is the change in cerebral blood flow (CBF) in response to a change in a vasoactive stimulus. Paradoxical reductions in CBF in response to vasodilatory stimulation (‘steal’) are associated with vascular pathology. However, a pathophysiological interpretation of ‘steal’ requires a comprehensive conceptual model linking pathology and changes in blood flow. Herein, we extend a simple model explaining steal published in the late 1960s by incorporating concepts of CBF regulation from more recent studies to generate a comprehensive dynamic model.

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The Dynamics of Cerebrovascular Reactivity Shown with Transfer Function Analysis

J Duffin, O Sobczyk, A P Crawley, J Poublanc, D J Mikulis, J A Fisher. Neuroimage. 2015 Jul 1;114:207-16. doi: 10.1016/j.neuroimage.2015.04.029. Epub 2015 Apr 16.
Cerebrovascular reactivity (CVR) is often defined as the increase in cerebral blood flow (CBF) produced by an increase in carbon dioxide (CO2) and may be used clinically to assess the health of the cerebrovasculature. When CBF is estimated using blood oxygen level dependent (BOLD) magnetic resonance imaging, CVR values for each voxel can be displayed using a color scale mapped onto the corresponding anatomical scan.

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Identifying Significant Changes in Cerebrovascular Reactivity to Carbon Dioxide

O Sobczyk, A P Crawley, J Poublanc, K Sam, D M Mandell, D J Mikulis, J Duffin, J A Fisher. AJNR Am J Neuroradiol. 2016 May;37(5):818-24.
doi: 10.3174/ajnr.A4679. Epub 2016 Feb 4.
Background and purpose: Changes in cerebrovascular reactivity can be used to assess disease progression and response to therapy but require discrimination of pathology from normal test-to-test variability. Such variability is due to variations in methodology, technology, and physiology with time. With uniform test conditions, our aim was to determine the test-to-test variability of cerebrovascular reactivity in healthy subjects and in patients with known cerebrovascular disease.

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Development of White Matter Hyperintensity is Preceded by Reduced Cerebrovascular Reactivity

Kevin Sam, Adrian P Crawley, John Conklin, Julien Poublanc, Olivia Sobczyk, Daniel M Mandell, Lakshmikumar Venkatraghavan, James Duffin, Joseph A Fisher, Sandra E Black, David J Mikulis. Ann Neurol. 2016 Aug;80(2):277-85. doi: 10.1002/ana.24712.
Objective: White matter hyperintensities (WMH) observed on neuroimaging of elderly individuals are associated with cognitive decline and disability. However, the pathogenesis of WMH remains poorly understood. We observed that regions of reduced cerebrovascular reactivity (CVR) in the white matter of young individuals correspond to the regions most susceptible to WMH in the elderly. This finding prompted us to consider that reduced CVR may play a role in the pathogenesis of WMH. We hypothesized that reduced CVR precedes development of WMH.

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Cerebrovascular Reactivity and White Matter Integrity

Kevin Sam, Boris Peltenburg, John Conklin, Olivia Sobczyk, Julien Poublanc, Adrian P Crawley, Daniel M Mandell, Lakshmikumar Venkatraghavan, James Duffin, Joseph A Fisher, Sandra E Black, David J Mikulis. Neurology. 2016 Nov 29;87(22):2333-2339.
doi: 10.1212/WNL.0000000000003373. Epub 2016 Oct 28.
Objective: To compare the diffusion and perfusion MRI metrics of normal-appearing white matter (NAWM) with and without impaired cerebrovascular reactivity (CVR). Methods: Seventy-five participants with moderate to severe leukoaraiosis underwent blood oxygen level-dependent CVR mapping using a 3T MRI system with precise carbon dioxide stimulus manipulation. Several MRI metrics were statistically compared between areas of NAWM with positive and negative CVR using one-way analysis of variance with Bonferroni correction for multiple comparisons.

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Assessing Cerebrovascular Reactivity Abnormality by Comparison to a Reference Atlas

Olivia Sobczyk, Anne Battisti-Charbonney, Julien Poublanc, Adrian P Crawley, Kevin Sam, Jorn Fierstra, Daniel M Mandell, David J Mikulis, James Duffin, Joseph A Fisher. J Cereb Blood Flow Metab. 2015 Feb;35(2):213-20. doi: 10.1038/jcbfm.2014.184. Epub 2014 Nov 12.
Attribution of vascular pathophysiology to reductions in cerebrovascular reactivity (CVR) is confounded by subjective assessment and the normal variation between anatomic regions. This study aimed to develop an objective scoring assessment of abnormality. CVR was measured as the ratio of the blood-oxygen-level-dependent magnetic resonance signal response divided by an increase in CO2, standardized to eliminate variability.

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