Cerebral Blood Flow and CO2 Reactivity in Transient Ischemic Attacks: Comparison between TIAs due to the ICA Occlusion and ICA Mild Stenosis

Hemispheric mean cerebral blood flow (CBF), together with its CO₂ reactivity in response to hyperventilation, was investigated in 18 patients with transient ischemic attacks (TIAs) by intraarterial ₁₃₃Xe injection method in a subacute-chronic stage of the clinical course. In 8 patients, the lesion responsible for symptoms was regarded as unilateral internal carotid artery (ICA) occlusion, and in 10 patients, it was regarded as unilateral ICA mild stenosis <50% stenosis in diameter). Resting flow values were significantly (P < 0.05) decreased in the affected hemisphere of TIA due to the ICA occlusion as compared with the unaffected hemisphere of the same patient, regarded as the relative control. It was not decreased in the affected hemisphere of TIA due to the ICA mild stenosis as compared with the control. With respect to the responsiveness of CBF to changes in Pa_CO2, it was preserved in both TIAs, due to the ICA occlusion and ICA mild stenosis. Vasoparalysis was not observed in either types of TIAs in the subacute-chronic stage. However, in the relationship of blood pressure and CO₂ reactivity, expressed as ΔCBF(%)/ΔPa_CO2, pressure-dependent CO₂ reactivity as a group was observed with significance (P < 0.05) in 8 cases of TIA due to the ICA occlusion, while no such relationship was noted in 10 cases of TIA due to the ICA mild stenosis. Moreover, clinical features were different between TIAs due to the ICA occlusion and ICA mild stenosis, i.e., more typical, repeatable TIA (6.3 ± 3.7 times) with shorter duration (<30 minutes) was observed in TIAs due to the ICA mild stenosis, while more prolonged, less repeatable TIA (2.4 ± 1.4 times) was observed in TIAs due to fixed obstruction of the ICA. From these observations, two different possible mechanisms as to the pathogenesis of TIA might be expected, e.g., TIA of microembolic origin due to the ICA mild stenosis, and TIA of hemodynamic origin due to fixed obstruction of the ICA, for whom the bypass surgery might be beneficial, i.e., all TIAs are not based on the same mechanism.     

Bi-hemispheric CBF and its CO2 reactivity of TIAs and completed strokes in ICA occlusions

Bi-hemispheric cerebral blood flow (CBF) measurements during rest and hyperventilation, with intra-arterial 133Xe injection method, were investigated in 19 cases, angiographically diagnosed as unilateral internal carotid artery (ICA) occlusion, including 8 cases with TIAs and 11 cases with completed strokes as the onset. Indices of cerebral vascular resistance and CO2 reactivity with decreasing arterial PCO2 were also investigated. A significant decrease (P less than 0.05) of hemispheric mean CBF was noted in the ischemic hemisphere, but normal flow values in the unaffected hemisphere and preserved CO2 responsiveness during hyperventilation were observed in both the affected and unaffected hemispheres in patients with TIAs. Moreover, a direct relationship between CBF and blood pressure, observed in 11 cases with completed strokes, was not recognized in 8 cases with TIAs. A degree of the abnormalities of the affected hemisphere in cerebral circulation was suggested to be somewhat different between TIAs and completed strokes in ICA occlusions, and bi-hemispheric CBF measurements would be an useful method for evaluating the various indices of the CBF in ICA occlusions.     

CO2 reactivity and autoregulation in fetal brain

Intraventricular hemorrhage (IVH) in preterm infants is well known to be associated with the high morbidity and mortality of this group. Previous studies have suggested altered cerebral blood flow (CBF) as an important pathologic factor. We measured the CBF in nearterm rabbit fetuses using the hydrogen clearance technique. The local CBF of the rabbit fetuses was significantly low compared with that of the maternal rabbits. The response of CBF to changes in PaCO₂ was observed in rabbit fetuses. The CO₂ reactivity index of the fetal rabbit was lower than that of the maternal rabbit. This low CO₂ reactivity might reflect the immaturity of the fetal brain and its low CBF. We were unable to monitor the fetal blood pressure, but the fetal CBF remained stable when the maternal blood pressure was altered. It is well known that IVH in preterm infants originates from the subependymal germinal matrix and that this has many fragile vessels. Our observation suggests that even a small increase of CBF during hypercapnia might have a large effect towards producing hemorrhage.     

Delayed recovery of CO2 reactivity after one hour's complete ischaemia of cat brain

Summary The cerebrovascular CO₂ reactivity was examined after 6h, 1, 2, and 3 days and 1 year following 1h complete brain ischaemia in the cat. After 6h recirculation, the CO₂ reactivity was completely suppressed although major EEG activity had recovered. After 2 days, CO₂ reactivity began to reappear, but even after 1 year restitution was not complete. The prolonged (though partly reversible) attenuation of CO₂ responsiveness suggests that ischaemia is followed by a long-lasting state of haemodynamic imbalance, which may be responsible for the slow progress of post-ischaemic recovery processes.     

Assessment of cerebrovascular reserve in unilateral middle cerebral artery stenosis using perfusion CT and CO2 inhalation tests

Purpose/Aim of the study: Cerebrovascular reactivity (CVR) is an important marker for assessing cerebrovascular disease. This study assessed the CVR by perfusion computed tomography (CT) and CO₂ inhalation tests in patients with unilateral middle cerebral artery (MCA) stenosis disease. Materials and Methods: Thirty-one patients with unilateral MCA stenosis disease diagnosed by digital subtraction angiography were studied. Patients were divided into two groups according to the degree of stenosis: severe and moderate. The regional cerebral blood flow (CBF) before and after CO₂ inhalation was determined by perfusion CT. Regional CVR values were obtained by the following formula: increase (%) = (post-CBF) ? (pre-CBF)/(pre-CBF) × 100%. Results: No significant differences in the mean CBF in the MCA stenosis region were found between the affected and contralateral sides before the CO₂ inhalation test; after the test, CBF was more significantly decreased on the affected side than on the contralateral side. The changes in CBF on the affected side were categorized into three types: increased CBF (17 cases), decreased CBF (12 cases) and no change in CBF (2 cases). The rate of CVR impairment among severe stenosis patients (13/19) was higher than that among moderate stenosis patients (3/12). CVR was significantly correlated with the degree of stenosis (r = 0.423, P = 0.018). Conclusion: CVR impairment was found in approximately half of patients with unilateral MCA stenosis. Along with an increase in the degree of stenosis, patients with unilateral MCA stenosis were more likely to exhibit CVR impairment. It is important to assess the CVR in patients with unilateral MCA stenosis, especially those with severe stenosis.     

CO2 has no therapeutic effect on early microvasospasm after experimental subarachnoid hemorrhage

In addition to delayed vasospasm also early brain injury, which occurs during the first few days after subarachnoid hemorrhage (SAH) when large cerebral arteries are still fully functional, plays an important role for the outcome after SAH. In the current study, we investigated the hypothesis that carbon dioxide (CO₂), a strong cerebral vasodilator, has a therapeutic potential against early posthemorrhagic microvasospasm. C57BL/6 mice (n=36) and Sprague-Dawley rats (n=23) were subjected to sham surgery or SAH by filament perforation. The pial microcirculation in the mice was visualized 3 and 24 hours after SAH using intravital fluorescence microscopy. Partial pressure of CO₂ (PaCO₂) was modulated by hyper- or hypoventilation or by inhalation of 10% CO₂. In rats, CO₂-mediated changes in cerebral blood flow (CBF) were measured at the same time points using laser Doppler fluxmetry. Increased PaCO₂ caused vasodilatation in sham-operated animals. Following SAH, however, cerebral arterioles were nonreactive to CO₂. This lack of microvascular CO₂ reactivity was accompanied by a complete loss of CO₂-induced hyperemia. Our data show that CO₂ is not able to dilate spastic microvessels and to increase CBF early after SAH. Future therapeutic approaches will therefore need to address mechanisms beyond CO₂.     

Effects of cerebrovascular autoregulation and CO2 reactivity in experimental localized brainstem infarction

Abstract

Using the previously reported method of experimental localized brainstem infarct in dogs, we designed this study to elucidate sequential changes of regional cerebral blood flow (rCBF) in three separate regions of the central nervous system: the cerebral cortex, thalamus, and midbrain. The data obtained were referred to in subsequent investigations of cerebrovascular autoregulation and vasomotor reactivity to C0₂. Localized brainstem infarct was produced by permanently occluding the perforators of the posterior cerebral arteries between the bilateral origins of the posterior communicating arteries. The hydrogen clearance method was applied to measure rCBF. Cerebrovascular autoregulation and CO₂ reactivity were assessed in three regions 1, 3, and 5 h after vascular occlusion, respectively. Vascular occlusion resulted in a decrease of rCBF that was 65% in the midbrain and close to 30%–40% in the thalamus. However, no significant change was seen in the cerebral cortex even 5 h after vascular occlusion. Induced hypertension impaired autoregulation in the thalamus, while it was preserved in the cerebral cortex. Induced hypotension did not alter autoregulation in any of the three regions. A marked loss of CO₂ reactivity was observed in the ischemic brainstem, although it was well preserved in the cerebral cortex. The results suggest that noradrenergic fibers originating from the cervical sympathetic ganglia play a main role in the cerebrovascular autoregulation in the cerebral cortex, while noradrenergic fibers possibly originating from the autonomic centers in the brainstem are responsible in the thalamus; that the noradrenergic neuron probably is not involved in the maintenance of cerebral blood flow during hypotension; and that the effect of CO₂ is mediated by its direct effect on the arteriolar wall in the central nervous system. [Neurol Res 2000; 22: 197–203]     

Global cerebral oxidative metabolism during hypercapnia and hypocapnia in humans: implications for BOLD fMRI

The effect of carbon dioxide (CO₂) on cerebral metabolism is of tremendous interest to functional imaging. In particular, mild-to-moderate hypercapnia is routinely used in calibrated blood oxygen-level dependent (BOLD)-functional magnetic resonance imaging (fMRI)-based quantification of cerebral oxidative metabolism changes (ΔCMRO₂), and relies on the assumption of a stable CMRO₂ during CO₂ challenges. However, this assumption has been challenged by certain animal studies, necessitating its verification in humans and under conditions customary to fMRI. We report, for the first time, on global ΔCMRO₂ measurements made noninvasively in humans during graded hypercapnia and hypocapnia. We used computerized end-tidal CO₂ modulation to minimize undesired concurrent changes in oxygen pressure, and our findings suggest that no significant change in global CMRO₂ is expected at the levels of end-tidal CO₂ changes customary to calibrated BOLD.     

Body fluids after CO2 inhalation: Insight into panic mechanisms?

Summary Blood gases and electrolyte fluctuations were studied in arterial blood, after a single 35% CO₂–65% O₂ inhalation, which is known to trigger panic attacks in patients with panic disorder. The immediate effect of this maneuver was a brief hypercapnic acidosis followed by a slight alkalotic rebound, with shifts in Ca²⁺ and K⁺. The possible effect of these changes on neuronal membrane excitability is discussed, referring to recent experimental findings in panic provocation.     

Role of prostacyclin in the response of cerebral blood flow to CO2

The prostacyclin (PGI₂) formation in cerebral vessels, as reflected by the difference in concentration of internal carotid arterial and internal jugular venous radioimmunoassayed 6-keto-prostaglandin F_1α (6-keto-PGF_1α), was determined under normocapnic and hypercapnic conditions in 5 patients with mild cerebral thrombotic infarction. There was no evidence that endogenous PGI₂ formation in cerebral vessels was stimulated at mild hypercapnia, while an increase of cerebral blood flow (CBF) induced by hypercapnia was observed.These results suggest that endogenous PGI₂ may not be a mediator for the response of CBF to CO₂.     

The four-dimensional stress test: psychological, sympathetic-adrenal-medullary, parasympathetic and hypothalamic-pituitary-adrenal responses following inhalation of 35% CO2

BACKGROUND: Hypercapnia is a threat to homeostasis and results in neuroendocrine, autonomic and anxiogenic responses. The inhalation of carbon dioxide (CO2) may, therefore, provide a good paradigm for exploring the pathways by which stress can lead to increased susceptibility to ill-health through physiological and psychological stress reactivity. The current study was designed, therefore, to assess the psychological and physiological responses to the inhalation of CO2. METHODS: Healthy participants (N = 24) inhaled a single vital capacity breath of a mixture of CO2 (35%) and oxygen (65%). Blood pressure and heart rate were recorded for 5 min before and after the test and blood and saliva samples were taken immediately before and 2, 10, 20 and 30 min post-inhalation for the measurement of noradrenaline, salivary and serum cortisol and salivary alpha amylase. In addition, psychosomatic symptoms were recorded immediately before and after the test. The same protocol was repeated 4-6 weeks later at the same time of day. RESULTS: A single inhalation of CO2 increased blood pressure, noradrenaline, salivary alpha amylase and psychosomatic symptoms, but decreased heart rate at both testing sessions. Analyses of salivary cortisol data revealed that 70% of the sample could be reliably classified as either responders (i.e. demonstrated a post-CO2 cortisol increase) or non-responders (i.e. responded with a decrease or no change in cortisol following CO2) at both test sessions. Responders also perceived the test to be more aversive than non-responders. CONCLUSIONS: Inhalation of 35% CO2 reliably stimulated the key mechanisms involved in the human stress response. The inter-individual differences in the reactivity of the hypothalamic-pituitary-adrenal axis were also related to differences in the perception of the test.     

Total excision of spinal lipomas using CO2 laser at low power. Experimental and clinical observations

Total excision of spinal lipomas (SL) is difficult because of the intimate adhesion between the fibro-adipose tissue and the neural structures. Radical surgery in SL can provoke nervous lesions; therefore many authors recommend only partial excision as a means of decompression. Nevertheless the role of traction or tethering of the spinal cord in all spinal disraphism, including SL, is known to be very important in determining the clinical picture. So partial removal of SL cannot be effective in releasing the tethered cord. The use of a CO₂ laser at low power (3-5 W) permitted radical surgery without any neural damage and complications in 2 adult patients with large, not well capsulated SL. These patients were previously operated on by the same surgeon with conventional microsurgical techniques for partial excision. After CO₂ laser surgery there was significant improvement of the clinical pictures, the follow-up being respectively 24 and 36 months. This clinical experience was performed after a CO₂ laser had successfully been used in an experimental model in rats simulating a condition of SL. Using power of 3-5 W was not sufficient to attain an immediate vaporization, but the adipose tissue first changed into a transparent liquidacross which it was possible to recognize the interfaces between the neural structures and the adipose tissue.     

Cerebrovascular consequences of altering serotonergic transmission in conscious rat

Many therapeutic strategies aim at altering serotonin brain levels. However, serotonin (5-HT) is known to influence the cerebral circulation. The purpose of this study was to determine the effects of acutely decreasing intracerebral serotonin release upon cerebral blood flow and cerebrovascular reactivity to hypercapnia in conscious rats. To this end, (1) we analyzed the time-course of cortical blood flow changes measured with laser-Doppler flowmetry following injection of 0.1 mg kg⁻¹ 8-OHDPAT (5-HT_1A agonist), and (2) we evaluated the cerebrovascular reactivity to hypercapnia using a quantitative multiregional diffusible tracer technique 5 and 60 min following 8-OHDPAT administration. 8-OHDPAT induced a rapid and transient increase in cortical blood flow (+34%) that was prevented totally by WAY100135 (5-HT_1A antagonist) pre-treatment. Five min following 8-OHDPAT administration, the cerebrovascular responsiveness to hypercapnia was increased significantly in striatum (+27%) and fronto-parietal cortex (+61%). This result is consistent with a vasoconstrictor role of the serotonergic system that becomes manifest during hyperemic conditions.     

Influence of cerebrovascular reactivity on outcome of the patients with ≥50% symptomatic unilateral middle cerebral artery stenosis

Purpose/aim of the study: Cerebrovascular reactivity (CVR) reflects the vasodilatory reserve of cerebral resistance vessels, which is an important marker for assessing cerebrovascular disease. The present study is to investigate whether CVR impairment increases adverse long-term outcome risk of patients with ≥ 50% symptomatic unilateral middle cerebral artery (MCA) stenosis (ischemic stroke (IS) or transient ischemic attack (TIA)).

Material and methods: Digital subtraction angiography (DSA) was used to assess the degree of stenosis, and perfusion CT and 5% CO₂ inhalation were adopted to evaluate CVR. Patients with ≥ 50% symptomatic unilateral MCA stenosis were assigned to non-CVR impairment group and CVR impairment group according to CVR status. The long-term follow-up endpoint was composite of any IS ( in the territory of the studied MCA) or death within 12 months.

Results: Seventy-three patients with ≥ 50% symptomatic unilateral MCA stenosis, involving 31 non-CVR impairment cases and 42 CVR impairment cases, were included in the present study. Finally, IS occurred in six CVR impairment patients, and no endpoint happened in the non-CVR impairment group. Therefore, the annual rate of IS was 14.29% in the CVR impairment group and 0% in the non-CVR impairment group (P = 0.035). Besides, further Kaplan-Meier analysis found CVR impairment was closely associated with the IS risk (Kaplan-Meier Log-rank 4.719, P = 0.030).

Conclusions: Our results showed that for patients with ≥ 50% symptomatic unilateral MCA stenosis, there was significant difference between non-CVR impairment cases and CVR impairment cases in the annual rate of IS. It suggests that CVR impairment increases the risk of adverse long-term outcomes.     

Repeated exposure to 20% CO2 challenge and risk for developing panic attacks: a controlled 6- and 12-month follow-up in a nonclinical sample

Among ethical concerns associated with biological challenge procedures is the risk of potentiating panic attacks in otherwise healthy persons who have no history of panic. The aim of the present study was to determine if repeated exposure to 20% CO2 challenge increases the risk of developing panic attacks in a nonclinical sample. One hundred and fifty-five (39.5%) of 392 participants who underwent a 20% CO2 challenge procedure and 51 (63.0%) of 81 controls who breathed only room air were evaluated for panic attacks using the Panic Attack Questionnaire-Revised both at 6 and 12 months after the experiment. The percentage of participants who developed subsequent panic attacks did not differ significantly between the CO2 challenge group and the room air controls. High dose CO2 challenge does not increase the risk of subsequent panic attacks in nonclinical populations; it is a safe paradigm for use in psychopathology research with healthy individuals.     

The effect of basal vasodilation on hypercapnic and hypocapnic reactivity measured using magnetic resonance imaging

Cerebrovascular reactivity to vasodilatory hypercapnic and vasoconstrictive hypocapnic challenges is known to be altered in several hemodynamic disorders, which is often attributable to changes in smooth muscle-mediated vascular compliance. Recently, attenuated reactivity to hypercapnia but enhanced reactivity to hypocapnia was observed in patients with chronic stroke. We hypothesize that the latter observation could be explained by a change in the basal vascular tone. In particular, reduced cerebral perfusion pressure, as is prevalent in these patients, may cause vasodilation through autoregulatory mechanisms, and this compensatory baseline condition may alter reactivity to vasoconstrictive hypocapnic challenges. To test this hypothesis, a predilated vascular condition was created in young, healthy subjects (n=11; age=23 to 36 years) using inhalation of 4% CO₂. Using blood oxygenation level-dependent functional magnetic resonance imaging at 3 T, breath holding and cued deep breathing respiratory challenges were administered to assess hypercapnia and hypocapnia reactivity, respectively. During the predilated condition, vasoconstrictive reactivity to hypocapnia was significantly (21.1%, P=0.016) enhanced throughout the gray matter, whereas there was no significant change (6.4%, P=0.459) in hypercapnic vasodilatory reactivity. This suggests that baseline vasodilation may explain the enhanced hypocapnia reactivity observed in some stroke patients, and that hypocapnia challenges may help identify the level of vascular compliance in patients with reduced cerebral perfusion pressure.     

Cerebrovascular reactivity is increased with acclimatization to 3,454?m altitude

Controversy exists regarding the effect of high-altitude exposure on cerebrovascular CO₂ reactivity (CVR). Confounding factors in previous studies include the use of different experimental approaches, ascent profiles, duration and severity of exposure and plausibly environmental factors associated with altitude exposure. One aim of the present study was to determine CVR throughout acclimatization to high altitude when controlling for these. Middle cerebral artery mean velocity (MCAv_mean) CVR was assessed during hyperventilation (hypocapnia) and CO₂ administration (hypercapnia) with background normoxia (sea level (SL)) and hypoxia (3,454 m) in nine healthy volunteers (26±4 years (mean±s.d.)) at SL, and after 30 minutes (HA0), 3 (HA3) and 22 (HA22) days of high-altitude (3,454 m) exposure. At altitude, ventilation was increased whereas MCAv_mean was not altered. Hypercapnic CVR was decreased at HA0 (1.16%±0.16%/mm Hg, mean±s.e.m.), whereas both hyper- and hypocapnic CVR were increased at HA3 (3.13%±0.18% and 2.96%±0.10%/mm Hg) and HA22 (3.32%±0.12% and 3.24%±0.14%/mm Hg) compared with SL (1.98%±0.22% and 2.38%±0.10%/mm Hg; P<0.01) regardless of background oxygenation. Cerebrovascular conductance (MCAv_mean/mean arterial pressure) CVR was determined to account for blood pressure changes and revealed an attenuated response. Collectively our results show that hypocapnic and hypercapnic CVR are both elevated with acclimatization to high altitude.     

Experiential,autonomic, and respiratory correlates of CO2 reactivity in individuals with high and low anxiety sensitivity

Psychometric studies indicate that anxiety sensitivity (AS) is a risk factor for anxiety disorders such as panic disorder (PD). To better understand the psychophysiological basis of AS and its relation to clinical anxiety, we examined whether high-AS individuals show similarly elevated reactivity to inhalations of carbon dioxide (CO₂) as previously reported for PD and social phobia in this task. Healthy individuals with high and low AS were exposed to eight standardized inhalations of 20% CO₂-enriched air, preceded and followed by inhalations of room air. Anxiety and dyspnea, in addition to autonomic and respiratory responses were measured every 15 s. Throughout the task, high AS participants showed a respiratory pattern of faster, shallower breathing and reduced inhalation of CO₂ indicative of anticipatory or contextual anxiety. In addition, they showed elevated dyspnea responses to the second set of air inhalations accompanied by elevated heart rate, which could be due to sensitization or conditioning. Respiratory abnormalities seem to be common to high AS individuals and PD patients when considering previous findings with this task. Similarly, sensitization or conditioning of anxious and dyspneic symptoms might be common to high AS and clinical anxiety. Respiratory conditionability deserves greater attention in anxiety disorder research.     

Dysfunction of mouse cerebral arteries during early aging

Aging leads to a gradual decline in the fidelity of cerebral blood flow (CBF) responses to neuronal activation, resulting in an increased risk for stroke and dementia. However, it is currently unknown when age-related cerebrovascular dysfunction starts or which vascular components and functions are first affected. The aim of this study was to examine the function of microcirculation throughout aging in mice. Microcirculation was challenged by inhalation of 5% and 10% CO₂ or by forepaw stimulation in 6-week, 8-month, and 12-month-old FVB/N mice. The resulting dilation of pial vessels and increase in CBF was measured by intravital fluorescence microscopy and laser Doppler fluxmetry, respectively. Neurovascular coupling and astrocytic endfoot Ca²⁺ were measured in acute brain slices from 18-month-old mice. We did not reveal any changes in CBF after CO₂ reactivity up to an age of 12 months. However, direct visualization of pial vessels by in vivo microscopy showed a significant, age-dependent loss of CO₂ reactivity starting at 8 months of age. At the same age neurovascular coupling was also significantly affected. These results suggest that aging does not affect cerebral vessel function simultaneously, but starts in pial microvessels months before global changes in CBF are detectable.