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Background Both obstructive sleep apnea (OSA) and altered cerebrovascular reactivity (CVR) are associated with increased stroke risk. Nevertheless, the incidence of abnormal CVR in patients with OSA is uncertain due to the high variability in the way CVR is measured both within and between studies. We hypothesized that a standardized CVR with a consistent vasoactive stimulus and cerebral blood flow (CBF) measure would be reduced in patients with severe OSA compared with healthy controls. Methods This was a prospective study in which subjects with and without OSA were administered a standardized hypercapnic stimulus, and CBF was monitored by blood oxygen level-dependent magnetic resonance signal changes, a high space and time resolved surrogate for CBF. Results Twenty-four subjects with OSA (mean age 45.9 years, apnea–hypopnea index [AHI] 26.8 per hour) and 6 control subjects (mean age 42.8 years, AHI 2.4 per hour) were included. Compared with controls, subjects with OSA had a significantly greater whole brain (.1565 versus .1094, P = .013), gray matter (.2077 versus .1423, P = .009), and white matter (.1109 versus .0768, P = .024) CVR, respectively. Conclusions Contrary to expectations, subjects with OSA had greater CVR compared with control subjects.

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. The main elements of the model are: (a) the relationship between changes in CBF and the arterial partial pressure of carbon dioxide (PaCO₂) in healthy vascular regions is sigmoidal; (b) vascular regions vasodilate to compensate for decreased perfusion pressure, leading to (c) an encroachment on vasodilatory reserve and, reduced CVR; (d) a vasodilatory stimulus may increase CBF capacity above the flow capacity of major cerebral blood vessels; and (e) this limitation induces competitive intra-cerebral redistribution of flow from territories with low vasodilatory reserve to those with high reserve. We used CVR measurements generated by applying precise, computer-controlled changes in PaCO₂ as the vasoactive stimulus, and measured blood oxygen level dependent (BOLD) MRI signals as high resolution surrogates of CBF to test predictions derived from this model. Subjects were 16 healthy adults and 16 patients with known cerebral steno-occlusive diseases. We observed regional sigmoidal PaCO₂-BOLD response curves with a range of slopes; graded changes in PaCO₂ resulted in redistributions of BOLD signal consistent with the known underlying vascular pathology and predictions of the model. We conclude that this model can be applied to provide a hemodynamic interpretation to BOLD signal changes in response to hypercapnia, and thereby aid in relating CVR maps to pathophysiological conditions.

Both obstructive sleep apnoea (OSA) and impaired cerebrovascular reactivity (CVR) are associated with an increased risk of stroke. We therefore hypothesized that CVR would be decreased in OSA patients. Since OSA is associated with altered endothelial function and this dysfunction may in turn lead to impaired CVR, we further hypothesized that a CVR decrease could be the responsible mechanism for stroke. Middle cerebral artery blood flow velocity (MCAv) and mean arterial blood pressure (MAP) responses to hypercapnia were measured to determine cerebrovascular conductance (MCAv/MAP). Overnight changes in conductance CVR were assessed in treatment naive, otherwise healthy OSA ( n = 13) and non-OSA ( n = 9) subjects at two isoxic tensions (150 and 50 mmHg). We found no significant overnight changes in CVR for either group. There were no differences in CVR between OSA and non-OSA subjects for either isoxic tension, although CVR was increased in hypoxia.

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.

We simultaneously measured respiratory, cerebrovascular and cardiovascular responses to 10-min of isoxic hypoxia at three constant CO(2) tensions in 15 subjects. We observed four response patterns, some novel, for ventilation, middle cerebral artery blood flow velocity, heart rate and mean arterial blood pressure. The occurrence of the response patterns was correlated between some measures. Isoxic hyperoxic and hypoxic ventilatory sensitivities to CO(2) derived from these responses were equivalent to those measured with modified (Duffin) rebreathing tests, but cerebrovascular sensitivities were not. We suggest the different ventilatory response patterns reflect the time course of carotid body afferent activity; in some individuals, carotid body function changes during hypoxia in more complex ways than previously thought. We concluded that isoxic hyperoxic and hypoxic ventilatory sensitivities to CO(2) can be measured using multiple hypoxic ventilatory response tests only if care is taken choosing the isocapnic CO(2) levels used, but a similar approach to measuring the cerebrovascular response to isocapnic hyperoxia and hypoxia is unfeasible.

Carbon dioxide (CO2) increases cerebral blood flow and arterial blood pressure. Cerebral blood flow increases not only due to the vasodilating effect of CO2 but also because of the increased perfusion pressure after autoregulation is exhausted. Our objective was to measure the responses of both middle cerebral artery velocity (MCAv) and mean arterial blood pressure (MAP) to CO2 in human subjects using Duffin-type isoxic rebreathing tests. Comparisons of isoxic hyperoxic with isoxic hypoxic tests enabled the effect of oxygen tension to be determined. During rebreathing the MCAv response to CO2 was sigmoidal below a discernible threshold CO2 tension, increasing from a hypocapnic minimum to a hypercapnic maximum. In most subjects this threshold corresponded with the CO2 tension at which MAP began to increase. Above this threshold both MCAv and MAP increased linearly with CO2 tension. The sigmoidal MCAv response was centred at a CO2 tension close to normal resting values (overall mean 36 mmHg). While hypoxia increased the hypercapnic maximum percentage increase in MCAv with CO2 (overall means from76.5 to 108%) it did not affect other sigmoid parameters. Hypoxia also did not alter the supra-threshold MCAv and MAP responses to CO2 (overall mean slopes 5.5% mmHg⁻¹ and 2.1 mmHg mmHg⁻¹, respectively), but did reduce the threshold (overall means from 51.5 to 46.8 mmHg). We concluded that in the MCAv response range below the threshold for the increase of MAP with CO2, the MCAv measurement reflects vascular reactivity to CO2 alone at a constant MAP.

Noninvasive monitoring of the arterial partial pressures of CO(2) (PaCO(2)) of critically ill patients by measuring their end-tidal partial pressures of CO(2) (PETCO(2)) would be of great clinical value. However, the gradient between PETCO(2) and PaCO(2) (PET-aCO(2)) in such patients typically varies over a wide range. A reduction of the PET-aCO(2) gradient can be achieved in spontaneously breathing healthy humans using an end-inspiratory rebreathing technique. We investigated whether this method would be effective in reducing the PET-aCO(2) gradient in a ventilated animal model.Six anesthetized pigs were ventilated mechanically. End-tidal gases were systematically adjusted over a wide range of PETCO(2) (30-55 mmHg) and PETO(2) (35-500 mmHg) while employing the end-inspiratory rebreathing technique and measuring the PET-aCO(2) gradient. Duplicate arterial blood samples were taken for blood gas analysis at each set of gas tensions.PETCO(2) and PaCO(2) remained equal within the error of measurement at all gas tension combinations. The mean ± SD PET-aCO(2) gradient (0.13 ± 0.12 mmHg, 95% CI -0.36, 0.10) was the same (p = 0.66) as that between duplicate PaCO(2) measurements at all PETCO(2) and PETO(2) combinations (0.19 ± 0.06, 95% CI -0.32, -0.06).The end-inspiratory rebreathing technique is capable of reducing the PET-aCO(2) gradient sufficiently to make the noninvasive measurement of PETCO(2) a useful clinical surrogate for PaCO(2) over a wide range of PETCO(2) and PETO(2) combinations in mechanically ventilated pigs. Further studies in the presence of severe ventilation-perfusion (V/Q) mismatching will be required to identify the limitations of the method.

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. A reference normal atlas was generated by coregistering the CVR maps from 46 healthy subjects into a standard space and calculating the mean and standard deviation (s.d.) of CVR for each voxel. Example CVR studies from 10 patients with cerebral vasculopathy were assessed for abnormality, by normalizing each patient's CVR to the same standard space as the atlas, and assigning a z-score to each voxel relative to the mean and s.d. of the corresponding atlas voxel. Z-scores were color coded and superimposed on their anatomic scans to form CVR z-maps. We found the CVR z-maps provided an objective evaluation of abnormality, enhancing our appreciation of the extent and distribution of pathophysiology compared with CVR maps alone. We concluded that CVR z-maps provide an objective, improved form of evaluation for comparisons of voxel-specific CVR between subjects, and across tests sites.

To evaluate the safety, tolerability, and technical feasibility of mapping cerebrovascular reactivity (CVR) in a clinical population by using a precise prospectively targeted CO(2) stimulus and blood oxygen level-dependent (BOLD) magnetic resonance (MR) imaging.A chart review was performed of all CVR studies from institutional review board-approved projects at a tertiary care hospital between January 1, 2006, and December 1, 2010. Informed consent was obtained. Records were searched for the incidence of adverse events and failed examinations. CVR maps were evaluated for diagnostic quality by two blinded observers and were categorized as good, diagnostic but suboptimal, or nondiagnostic. Outcomes were presented as raw data and descriptive statistics (means ± standard deviations). Intraclass correlation coefficient was used to determine interobserver variability.Four hundred thirty-four consecutive CVR examinations from 294 patients (51.8% female patients) were studied. Patient age ranged from 9 to 88 years (mean age, 45.9 years ± 20.6). Transient symptoms, such as shortness of breath, headache, and dizziness, were reported in 48 subjects (11.1% of studies) during hypercapnic phases only. There were no neurologic ischemic events, myocardial infarctions, or other major complications. The success rate in generating CVR maps was 83.9% (364 of 434). Of the 70 (16.1%) failed examinations, 25 (35.7%) were due to discomfort; eight (11.4%), to head motion; two (2.9%), to inability to cooperate; seven (10.0%), to technical difficulties with equipment; and 28 (40.0%), to unknown or unspecified conditions. Among the 364 remaining successful examinations, good quality CVR maps were obtained in 340 (93.4%); diagnostic but suboptimal, in 12 (3.3%); and nondiagnostic, in 12 (3.3%).CVR mapping by using a prospectively targeted CO(2) stimulus and BOLD MR imaging is safe, well tolerated, and technically feasible in a clinical patient population.

Because the skin is an oxygen sensor in amphibians and mice, we thought to confirm this function also in humans. The human upright posture, however, introduces additional functional demands for the maintenance of oxygen homeostasis in which cerebral blood flow and autonomic nervous system (ANS) function may also be involved. We examined nine males and three females. While subjects were breathing ambient air, at sea level, we changed gases in a plastic body-bag during two conditions of the experiment such as to induce skin hypoxia (with pure nitrogen) or skin normoxia (with air). The subjects performed a test of hypoxic ventilatory drive during each condition of the experiment. We found no differences in the hypoxic ventilatory drive tests. However, ANS function and cerebral blood flow velocities were modulated by skin hypoxia and the effect was significantly greater on the left than right middle cerebral arteries. We conclude that skin hypoxia modulates ANS function and cerebral blood flow velocities and this might impact life styles and tolerance to ambient hypoxia at altitude. Thus the skin in normal humans, in addition to its numerous other functions, is also an oxygen sensor.

Objectives Unilateral haemodynamically significant large-vessel intracranial stenosis may be associated with reduced blood-oxygen-level-dependent (BOLD) cerebrovascular reactivity (CVR), an indicator of autoregulatory reserve. Reduced CVR has been associated with ipsilateral cortical thinning and loss in cognitive function. These effects have been shown to be reversible following revascularisation. Our aim was to study the effects of unilateral revascularisation on CVR in the non-intervened hemisphere in bilateral steno-occlusive or Moyamoya disease. Study Design A retrospective observational study. Setting A routine follow-up assessment of CVR after a revascularisation procedure at a research teaching hospital in Toronto (Journal wants us to generalise). Participants Thirteen patients with bilateral Moyamoya disease (age range 18 to 52 years; 3 males), seven patients with steno-occlusive disease (age range 18 to 78 years; six males) and 27 approximately age-matched normal control subjects (age range 19–71 years; 16 males) with no history or findings suggestive of any neurological or systemic disease. Intervention Participants underwent BOLD CVR MRI using computerised prospective targeting of CO2, before and after unilateral revascularisation (extracranial–intracranial bypass, carotid endarterectomy or encephaloduroarteriosynangiosis). Pre-revascularisation and post-revascularisation CVR was assessed in each major arterial vascular territory of both hemispheres. Results As expected, surgical revascularisation improved grey matter CVR in the middle cerebral artery (MCA) territory of the intervened hemisphere (0.010±0.023 to 0.143±0.010%BOLD/mm Hg, p