Measuring cerebrovascular reactivity: what stimulus to use?

Abstract

Cerebrovascular reactivity is the change in cerebral blood flow in response to a vasodilatory or vasoconstrictive stimulus. Measuring variations of cerebrovascular reactivity between different regions of the brain has the potential to not only advance understanding of how the cerebral vasculature controls the distribution of blood flow but also to detect cerebrovascular pathophysiology. While there are standardized and repeatable methods for estimating the changes in cerebral blood flow in response to a vasoactive stimulus, the same cannot be said for the stimulus itself. Indeed, the wide variety of vasoactive challenges currently employed in these studies impedes comparisons between them. This review therefore critically examines the vasoactive stimuli in current use for their ability to provide a standard repeatable challenge and for the practicality of their implementation. Such challenges include induced reductions in systemic blood pressure, and the administration of vasoactive substances such as acetazolamide and carbon dioxide. We conclude that many of the stimuli in current use do not provide a standard stimulus comparable between individuals and in the same individual over time. We suggest that carbon dioxide is the most suitable vasoactive stimulus. We describe recently developed computer-controlled MRI compatible gas delivery systems which are capable of administering reliable and repeatable vasoactive CO2 stimuli.

Figure 1. Example CVR maps

CVR is the ratio of the change in the BOLD-MRI signal in response to a change in CO₂ stimulus, and is colour coded voxel by voxel according to the scale provided in the colour bar, and superimposed on the corresponding voxel of the anatomical scan. A, CVR map measured in a healthy volunteer. B, CVR map measured in a patient with moya moya disease. Although the hypercapnic stimulus was the same in each subject, the distribution of the changes in blood flow in the patient with moya moya disease revealed multiple areas of reduced cerebrovascular reactivity in response to the global vasodilatory stimulus. These regions of reduced CVR are the result of vascular steal, where stimulus-induced reductions in flow resistance result in flow diversion from regions of low to high vasodilatory reactivity.

Figure 2. The sequential gas delivery circuit (SGD) operation

The valve manifold has an inspiratory valve (1), an expiratory valve (2) and a cross-over valve (3). The latter has a slightly greater opening pressure than the other valves and, when open allows gas to cross from the expiratory to the inspiratory limb. During expiration, gas delivered by the gas blender enters the inspiratory gas reservoir (green dotted line), and exhaled gas enters the expired gas reservoir (blue dashed line).During inspiration, gas is drawn from the stored blender gas in the inspiratory gas reservoir (green dotted lines). If the inspired volume exceeds the volume in the inspiratory reservoir, the balance comes from the expiratory gas reservoir via the cross-over valve (blue dashed line).

Figure 3. Examples of P_{E T, CO2} and P_{E T, O2} control in a subject using an SGD breathing circuit and prospective end-tidal targeting

The continuous traces from sampling at the mask are (blue upper) and (red lower). End-tidal values are (red filled squares) and (green filled circles), each representing a single breath. A, sinusoidal changes of and are implemented in phase until the blue arrow, when the phase of the is changed 180 deg. B, sinusoidal changes of and are implemented with the period of twice that of . C, simultaneous square wave changes in and are implemented independently of each other. In the sinusoidal patterns, the target and change with each breath. The algorithm used to reach these targets is context sensitive, that is, it takes into account the current gas concentrations in the lung as well as the target history. This means that the set of flows and inspired gas concentrations differ – even for the same recurrent end-tidal target values, whether they be in a sinusoidal sequence or steady target level. The algorithm uses the baseline , and resting CO₂ production and O₂ consumption to calculate inspired gas parameters. Baseline is based on the during rest. Resting CO₂ production and O₂ consumption are calculated from a nomogram based on sex, height and weight. Errors in presumption of CO₂ production or O₂ consumption, or changes in these due to changes in activity or muscle tone, result in target values drifting over time, as can be seen in A and C.

Figure 4. Voxel tracking of P_{E T, CO2}

CVR maps, constructed as for Fig. 1, are shown on the left with chosen voxels indicated by the cross-hairs. The right side shows graphs of the time course of the chosen voxels BOLD signals (blue dots) in response to the changes in (red dots). A, a voxel with positive CVR. B, a voxel with negative CVR (vascular steal). In each case the BOLD signals track the stimulus, indicating that a precise and accurate measurement of CVR requires accuracy and precision of the stimulus as well as the surrogate measure of cerebral blood flow.