Impaired cerebral autoregulation in obstructive sleep apnea

Obstructive sleep apnea (OSA) increases the risk of stroke independent of known vascular and metabolic risk factors. Although patients with OSA have higher prevalence of hypertension and evidence of hypercoagulability, the mechanism of this increased risk is unknown. Obstructive apnea events are associated with surges in blood pressure, hypercapnia, and fluctuations in cerebral blood flow. These perturbations can adversely affect the cerebral circulation. We hypothesized that patients with OSA have impaired cerebral autoregulation, which may contribute to the increased risk of cerebral ischemia and stroke. We examined cerebral autoregulation in patients with and without OSA by measuring cerebral artery blood flow velocity (CBFV) by using transcranial Doppler ultrasound and arterial blood pressure using finger pulse photoplethysmography during orthostatic hypotension and recovery as well as during 5% CO(2) inhalation. Cerebral vascular conductance and reactivity were determined. Forty-eight subjects, 26 controls (age 41.0+/-2.3 yr) and 22 OSA (age 46.8+/-2.3 yr) free of cerebrovascular and active coronary artery disease participated in this study. OSA patients had a mean apnea-hypopnea index of 78.4+/-7.1 vs. 1.8+/-0.3 events/h in controls. The oxygen saturation during sleep was significantly lower in the OSA group (78+/-2%) vs. 91+/-1% in controls. The dynamic vascular analysis showed mean CBFV was significantly lower in OSA patients compared with controls (48+/-3 vs. 55+/-2 cm/s; P <0.05, respectively). The OSA group had a lower rate of recovery of cerebrovascular conductance for a given drop in blood pressure compared with controls (0.06+/-0.02 vs. 0.20+/-0.06 cm.s(-2).mmHg(-1); P <0.05). There was no difference in cerebrovascular vasodilatation in response to CO(2). The findings showed that patients with OSA have decreased CBFV at baseline and delayed cerebrovascular compensatory response to changes in blood pressure but not to CO(2). These perturbations may increase the risk of cerebral ischemia during obstructive apnea.     

Influence of hypercapnic vasodilation on cerebrovascular autoregulation and pial arteriolar bed resistance in piglets.

Changes in both pial arteriolar resistance (PAR) and simulated arterial-arteriolar bed resistance (SimR) of a physiologically based biomechanical model of cerebrovascular pressure transmission, the dynamic relationship between arterial blood pressure and intracranial pressure, are used to test the hypothesis that hypercapnia disrupts autoregulatory reactivity. To evaluate pressure reactivity, vasopressin-induced acute hypertension was administered to normocapnic and hypercapnic (N = 12) piglets equipped with closed cranial windows. Pial arteriolar diameters were used to compute arteriolar resistance. Percent change of PAR (%DeltaPAR) and percent change of SimR (%DeltaSimR) in response to vasopressin-induced acute hypertension were computed and compared. Hypercapnia decreased cerebrovascular resistance. Indicative of active autoregulatory reactivity, vasopressin-induced hypertensive challenge resulted in an increase of both %DeltaPAR and %DeltaSimR for all normocapnic piglets. The hypercapnic piglets formed two statistically distinct populations. One-half of the hypercapnic piglets demonstrated a measured decrease of both %DeltaPAR and %DeltaSimR to pressure challenge, indicative of being pressure passive, whereas the other one-half demonstrated an increase in these percentages, indicative of active autoregulation. No other differences in measured variables were detectable between regulating and pressure-passive piglets. Changes in resistance calculated from using the model mirrored those calculated from arteriolar diameter measurements. In conclusion, vasodilation induced by hypercapnia has the potential to disrupt autoregulatory reactivity. Our physiologically based biomechanical model of cerebrovascular pressure transmission accurately estimates the changes in arteriolar resistance during conditions of active and passive cerebrovascular reactivity.     

Frequency response characteristics of cerebral blood flow autoregulation in rats

Transfer function analysis of blood pressure and cerebral blood flow in humans demonstrated that cerebrovascular autoregulation operates most effectively for slow fluctuations in perfusion pressure, not exceeding a frequency of approximately 0.15 Hz. No information on the dynamic properties of cerebrovascular autoregulation is available in rats. Therefore, we tested the hypothesis that cerebrovascular autoregulation in rats is also most effective for slow fluctuations in perfusion pressure below 0.15 Hz. Normotensive Wistar-Kyoto rats (n = 10) were instrumented with catheters in the left common carotid artery and jugular vein and flow probes around the right internal carotid artery. During isoflurane anesthesia, fluctuations in cerebral perfusion pressure were elicited by periodically occluding the abdominal aorta at eight frequencies ranging from 0.008 Hz to 0.5 Hz. The protocol was repeated during inhibition of myogenic vascular function (nifedipine, 0.25 mg/kg body wt iv). Increases in cerebral perfusion pressure elicited initial increases in cerebrovascular conductance and decreases in resistance. At low occlusion frequencies (<0.1 Hz), these initial responses were followed by decreases in conductance and increases in resistance that were abolished by nifedipine. At occlusion frequencies of 0.1 Hz and above, the gains of the transfer functions between pressure and blood flow and between pressure and resistance were equally high in the control and nifedipine trial. At occlusion frequencies below 0.1 Hz, the gains of the transfer functions decreased twice as much under control conditions than during nifedipine application. We conclude that dynamic autoregulation of cerebral blood flow is restricted to very low frequencies (<0.1 Hz) in rats.     

Increases in cerebrovascular impedance in older adults

This study explored a novel method for measuring cerebrovascular impedance to quantify the relationship between pulsatile changes in cerebral blood flow (CBF) and arterial pressure. Arterial pressure in the internal or common carotid artery (applanation tonometry), CBF velocity in the middle cerebral artery (transcranial Doppler), and end-tidal CO(2) (capnography) were measured in six young (28 ± 4 yr) and nine elderly subjects (70 ± 6 yr). Transfer function method was used to estimate cerebrovascular impedance. Under supine resting conditions, CBF velocity was reduced in the elderly despite the fact that they had higher arterial pressure than young subjects. As expected, cerebrovascular resistance index was increased in the elderly. In both young and elderly subjects, impedance modulus was reduced gradually in the frequency range of 0.78-8 Hz. Phase was negative in the range of 0.78-4.3 Hz and fluctuated at high frequencies. Compared with the young, impedance modulus increased by 38% in the elderly in the range of 0.78-2 Hz and by 39% in the range of 2-4 Hz (P < 0.05). Moreover, increases in impedance were correlated with reductions in CBF velocity. Collectively, these findings demonstrate the feasibility of assessing cerebrovascular impedance using the noninvasive method developed in this study. The estimated impedance modulus and phase are similar to those observed in the systemic circulation and other vascular beds. Moreover, increases in impedance in the elderly suggest that arterial stiffening, besides changes in cerebrovascular resistance, contributes to reduction in CBF with age.     

Morning attenuation in cerebrovascular CO2 reactivity in healthy humans is associated with a lowered cerebral oxygenation and an augmented ventilatory response to CO2.

We hypothesized that, in healthy subjects without pharmacological intervention, an overnight reduction in cerebrovascular CO(2) reactivity would be associated with an elevated hypercapnic ventilatory [ventilation (VE)] responsiveness and a reduction in cerebral oxygenation. In 20 healthy male individuals with no sleep-related disorders, continuous recordings of blood velocity in the middle cerebral artery, arterial blood pressure, VE, end-tidal gases, and frontal cortical oxygenation using near infrared spectroscopy were monitored during hypercapnia (inspired CO(2), 5%), hypoxia [arterial O(2) saturation (Sa(O(2))) approximately 84%], and during a 20-s breath hold to investigate the related responses to hypercapnia, hypoxia, and apnea, respectively. Measurements were conducted in the evening (6-8 PM) and in the early morning (6-8 AM). From evening to morning, the cerebrovascular reactivity to hypercapnia was reduced (5.3 +/- 0.6 vs. 4.6 +/- 1.1%/Torr; P < 0.05) and was associated with a reduced increase in cerebral oxygenation (r = 0.39; P < 0.05) and an elevated morning hypercapnic VE response (r = 0.54; P < 0.05). While there were no overnight changes in cerebrovascular reactivity or VE response to hypoxia, there was greater cerebral desaturation for a given Sa(O(2)) in the morning (AM, -0.45 +/- 0.14 vs. PM, -0.35 +/- 0.14%/Sa(O(2)); P < 0.05). Following the 20-s breath hold, in the morning, there was a smaller surge middle cerebral artery velocity and cerebral oxygenation (P < 0.05 vs. PM). These data indicate that normal diurnal changes in the cerebrovascular response to CO(2) influence the hypercapnic ventilatory response as well as the level of cerebral oxygenation during changes in arterial Pco(2); this may be a contributing factor for diurnal changes in breathing stability and the high incidence of stroke in the morning.     

Human cardiorespiratory and cerebrovascular function during severe passive hyperthermia: effects of mild hypohydration.

The influence of severe passive heat stress and hypohydration (Hypo) on cardiorespiratory and cerebrovascular function is not known. We hypothesized that 1) heating-induced hypocapnia and peripheral redistribution of cardiac output (Q) would compromise blood flow velocity in the middle cerebral artery (MCAv) and cerebral oxygenation; 2) Hypo would exacerbate the hyperthermic-induced hypocapnia, further decreasing MCAv; and 3) heating would reduce MCAv-CO2 reactivity, thereby altering ventilation. Ten men, resting supine in a water-perfused suit, underwent progressive hyperthermia [0.5 degrees C increments in core (esophageal) temperature (TC) to +2 degrees C] while euhydrated (Euh) or Hypo by 1.5% body mass (attained previous evening). Time-control (i.e., non-heat stressed) data were obtained on six of these subjects. Cerebral oxygenation (near-infrared spectroscopy), MCAv, end-tidal carbon dioxide (PetCO2) and arterial blood pressure, Q (flow model), and brachial and carotid blood flows (CCA) were measured continuously each 0.5 degrees C change in TC. At each level, hypercapnia was achieved through 3-min administrations of 5% CO2, and hypocapnia was achieved with controlled hyperventilation. At baseline in Hypo, heart rate, MCAv and CCA were elevated (P<0.05 vs. Euh). MCAv-CO2 reactivity was unchanged in both groups at all TC levels. Independent of hydration, hyperthermic-induced hyperventilation caused a severe drop in PetCO2 (-8+/-1 mmHg/ degrees C), which was related to lower MCAv (-15+/-3%/ degrees C; R2=0.98; P<0.001). Elevations in Q were related to increases in brachial blood flow (R2=0.65; P<0.01) and reductions in MCAv (R2=0.70; P<0.01), reflecting peripheral distribution of Q. Cerebral oxygenation was maintained, presumably via enhanced O2-extraction or regional differences in cerebral perfusion.     

Alterations in cerebral dynamics at high altitude following partial acclimatization in humans: wakefulness and sleep.

We tested the hypothesis that, following exposure to high altitude, cerebrovascular reactivity to CO2 and cerebral autoregulation would be attenuated. Such alterations may predispose to central sleep apnea at high altitude by promoting changes in brain PCO2 and thus breathing stability. We measured middle cerebral artery blood flow velocity (MCAv; transcranial Doppler ultrasound) and arterial blood pressure during wakefulness in conditions of eucapnia (room air), hypocapnia (voluntary hyperventilation), and hypercapnia (isooxic rebeathing), and also during non-rapid eye movement (stage 2) sleep at low altitude (1,400 m) and at high altitude (3,840 m) in five individuals. At each altitude, sleep was studied using full polysomnography, and resting arterial blood gases were obtained. During wakefulness and polysomnographic-monitored sleep, dynamic cerebral autoregulation and steady-state changes in MCAv in relation to changes in blood pressure were evaluated using transfer function analysis. High altitude was associated with an increase in central sleep apnea index (0.2 +/- 0.4 to 20.7 +/- 23.2 per hour) and an increase in mean blood pressure and cerebrovascular resistance during wakefulness and sleep. MCAv was unchanged during wakefulness, whereas there was a greater decrease during sleep at high altitude compared with low altitude (-9.1 +/- 1.7 vs. -4.8 +/- 0.7 cm/s; P < 0.05). At high altitude, compared with low altitude, the cerebrovascular reactivity to CO2 in the hypercapnic range was unchanged (5.5 +/- 0.7 vs. 5.3 +/- 0.7%/mmHg; P = 0.06), while it was lowered in the hypocapnic range (3.1 +/- 0.7 vs. 1.9 +/- 0.6%/mmHg; P < 0.05). Dynamic cerebral autoregulation was further reduced during sleep (P < 0.05 vs. low altitude). Lowered cerebrovascular reactivity to CO2 and reduction in both dynamic cerebral autoregulation and MCAv during sleep at high altitude may be factors in the pathogenesis of breathing instability.     

Syncope, cerebral perfusion, and oxygenation.

During standing, both the position of the cerebral circulation and the reductions in mean arterial pressure (MAP) and cardiac output challenge cerebral autoregulatory (CA) mechanisms. Syncope is most often associated with the upright position and can be provoked by any condition that jeopardizes cerebral blood flow (CBF) and regional cerebral tissue oxygenation (cO(2)Hb). Reflex (vasovagal) responses, cardiac arrhythmias, and autonomic failure are common causes. An important defense against a critical reduction in the central blood volume is that of muscle activity ("the muscle pump"), and if it is not applied even normal humans faint. Continuous tracking of CBF by transcranial Doppler-determined cerebral blood velocity (V(mean)) and near-infrared spectroscopy-determined cO(2)Hb contribute to understanding the cerebrovascular adjustments to postural stress; e.g., MAP does not necessarily reflect the cerebrovascular phenomena associated with (pre)syncope. CA may be interpreted as a frequency-dependent phenomenon with attenuated transfer of oscillations in MAP to V(mean) at low frequencies. The clinical implication is that CA does not respond to rapid changes in MAP; e.g., there is a transient fall in V(mean) on standing up and therefore a feeling of lightheadedness that even healthy humans sometimes experience. In subjects with recurrent vasovagal syncope, dynamic CA seems not different from that of healthy controls even during the last minutes before the syncope. Redistribution of cardiac output may affect cerebral perfusion by increased cerebral vascular resistance, supporting the view that cerebral perfusion depends on arterial inflow pressure provided that there is a sufficient cardiac output.     

Cerebral blood flow in diabetes mellitus: evidence of abnormal cerebrovascular reactivity.

Cerebral blood flow (CBF) was studied at normocapnia and after a challenge with 5% CO2 in 59 diabetic patients and 28 controls. There was a significant age-related decline in CBF in both groups, which suggests that diabetes does not affect the rate of decrease of CBF with age. After CO2 challenge CBF increased in most of the controls; in the patients CBF increased in 23, decreased in 26, and remained stable in 10. Thus the reactivity of cerebral blood vessels in diabetics is altered. Diabetics have diminished cerebrovascular reserve and are thus at increased risk of cerebrovascular disease because they are unable to compensate when necessary with an increased CBF.     

Impaired cerebrovascular autoregulation and reduced CO₂ reactivity after long duration spaceflight

Long duration habitation on the International Space Station (ISS) is associated with chronic elevations in arterial blood pressure in the brain compared with normal upright posture on Earth and elevated inspired CO(2). Although results from short-duration spaceflights suggested possibly improved cerebrovascular autoregulation, animal models provided evidence of structural and functional changes in cerebral vessels that might negatively impact autoregulation with longer periods in microgravity. Seven astronauts (1 woman) spent 147 ± 49 days on ISS. Preflight testing (30-60 days before launch) was compared with postflight testing on landing day (n = 4) or the morning 1 (n = 2) or 2 days (n = 1) after return to Earth. Arterial blood pressure at the level of the middle cerebral artery (BP(MCA)) and expired CO(2) were monitored along with transcranial Doppler ultrasound assessment of middle cerebral artery (MCA) blood flow velocity (CBFV). Cerebrovascular resistance index was calculated as (CVRi = BP(MCA)/CBFV). Cerebrovascular autoregulation and CO(2) reactivity were assessed in a supine position from an autoregressive moving average (ARMA) model of data obtained during a test where two breaths of 10% CO(2) were given four times during a 5-min period. CBFV and Doppler pulsatility index were reduced during -20 mmHg lower body negative pressure, with no differences pre- to postflight. The postflight indicator of dynamic autoregulation from the ARMA model revealed reduced gain for the CVRi response to BP(MCA) (P = 0.017). The postflight responses to CO(2) were reduced for CBFV (P = 0.056) and CVRi (P = 0.047). These results indicate that long duration missions on the ISS impaired dynamic cerebrovascular autoregulation and reduced cerebrovascular CO(2) reactivity.     

Changes in cerebral oxygenation and blood flow during LBNP in spinal cord-injured individuals.

Spinal cord-injured (SCI) individuals, having a sympathetic nervous system lesion, experience hypotension during sitting and standing. Surprisingly, they experience few syncopal events. This suggests adaptations in cerebrovascular regulation. Therefore, changes in systemic circulation, cerebral blood flow, and oxygenation in eight SCI individuals were compared with eight able-bodied (AB) individuals. Systemic circulation was manipulated by lower body negative pressure at several levels down to -60 mmHg. At each level, we measured steady-state blood pressure, changes in cerebral blood velocity with transcranial Doppler, and cerebral oxygenation using near-infrared spectroscopy. We found that mean arterial pressure decreased significantly in SCI but not in AB individuals, in accordance with the sympathetic impairment in the SCI group. Cerebral blood flow velocity decreased during orthostatic stress in both groups, but this decrease was significantly greater in SCI individuals. Cerebral oxygenation decreased in both groups, with a tendency to a greater decrease in SCI individuals. Thus present data do not support an advantageous mechanism during orthostatic stress in the cerebrovascular regulation of SCI individuals.     

WISE 2005: altered cerebrovascular autoregulation after 60 day head-down bed rest

We tested the hypothesis that 60 days of head-down bed rest (HDBR) would affect cerebrovascular autoregulation and that this change would be correlated with changes in tolerance to the upright posture. Twenty-four healthy women (32 +/- 4 yrs) participated in a 60-d bed rest study at the MEDES Clinic in Toulouse, France. End tidal CO2 (ETCO2), continuous blood pressure (BP), middle cerebral artery (MCA) velocity and time to presyncope (endpoint) were measured during an orthostatic tolerance test conducted before/after bed rest. Given the large range of change in tolerance even within assigned countermeasure groups, we separated subjects for this analysis on the basis of the change in endpoint (Delta endpoint) pre- to post-bed rest. Autoregulation and CO2 responsiveness were evaluated on a different day from a two-breath test with intermittent hypercapnic exposure. Autoregressive moving average (ARMA) modeled the two confounding inputs, BP and CO2, on cerebrovascular blood flow. The cerebrovascular resistance index (CVRi) was expected to decrease following a decrease in BP at the MCA to assist in maintenance of cerebral blood flow. Subjects with the smallest Delta endpoint after bed rest had a 78% increase in the gain of the BP --> CVRi response. Meanwhile, the groups with greater decline in orthostatic tolerance post-HDBR had no change in the gain of this response. ETCO2 was lower overall following HDBR, decreasing from 41.8 +/- 3.4 to 40.2 +/- 3.0 in supine rest, 37.9 +/- 3.4 to 33.3 +/- 4.0 in early tilt, and 29.5 +/- 4.4 to 27.1 +/- 5.1 at pre-syncope. There was however, higher MCA velocity at any ETCO2 for post- compared to pre-HDBR. In summary, changes in autoregulation were found only in those subjects who had the smallest change from pre- to post-HDBR orthostatic tolerance. The changes may assist in buffering changes in cerebral blood flow during orthostatic hypotension post-HDBR. The reduction in ETCO2 after bed rest might be due to a change in chemoreceptor response to blood CO2, but the cerebrovascular system seems to have completely compensated.     

Calcitonin Gene-Related Peptide (CGRP) Receptors Are Important to Maintain Cerebrovascular Reactivity in Chronic Hypertension

Cerebral blood flow autoregulation (CA) shifts to higher blood pressures in chronic hypertensive patients, which increases their risk for brain damage. Although cerebral vascular smooth muscle cells express the potent vasodilatatory peptides calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) and their receptors (calcitonin receptor-like receptor (Calclr), receptor-modifying proteins (RAMP) 1 and 2), their contribution to CA during chronic hypertension is poorly understood. Here we report that chronic (10 weeks) hypertensive (one-kidney-one-clip-method) mice overexpressing the Calclr in smooth muscle cells (CLR-tg), which increases the natural sensitivity of the brain vasculature to CGRP and AM show significantly better blood pressure drop-induced cerebrovascular reactivity than wt controls. Compared to sham mice, this was paralleled by increased cerebral CGRP-binding sites (receptor autoradiography), significantly in CLR-tg but not wt mice. AM-binding sites remained unchanged. Whereas hypertension did not alter RAMP-1 expression (droplet digital (dd) PCR) in either mouse line, RAMP-2 expression dropped significantly in both mouse lines by about 65%. Moreover, in wt only Calclr expression was reduced by about 70% parallel to an increase of smooth muscle actin (Acta2) expression. Thus, chronic hypertension induces a stoichiometric shift between CGRP and AM receptors in favor of the CGRP receptor. However, the parallel reduction of Calclr expression observed in wt mice but not CLR-tg mice appears to be a key mechanism in chronic hypertension impairing cerebrovascular reactivity.     

Nitric oxide, prostaglandins, and impaired cerebral blood flow autoregulation in group B streptococcal neonatal meningitis

Impaired autoregulation of cerebral blood flow (CBF) contributes to CNS damage during neonatal meningitis. We tested (i) the hypothesis that cerebrovascular autoregulation is impaired during early onset group B streptococcal (GBS) meningitis, (ii) whether this impairment is regulated by vasoactive mediators such as prostaglandins and (or) nitric oxide (NO), and (iii) whether this impairment is preventable by specific and (or) nonspecific inhibitors: dexamethasone, ibuprofen, and Nomega-nitro-L-arginine, a NO inhibitor. Sterile saline or 10(9) colony-forming units (cfu) of heat-killed GBS was injected into the cerebral ventricle of newborn piglets. CBF autoregulation was determined by altering cerebral perfusion pressure (CPP) with balloon-tipped catheters placed in the aorta. GBS produced a narrow range of CBF autoregulation due to an impairment at the upper limit of CPP. We report that in vivo in the early stages (first 2 h) of induced GBS inflammation (i) GBS impairs the upper limit of cerebrovascular autoregulation; (ii) ibuprofen, dexamethasone, and Nomega-nitro-L-arginine not only prevent this GBS-induced autoregulatory impairment but improve the range of cerebrovascular autoregulation; (iii) these autoregulatory changes do not involve circulating cerebral prostanoids; and (iv) the observed changes correlate with the induction of NO synthase gene expression. Thus, acute early onset GBS-induced impairment of the upper limit of CBF autoregulation can be correlated with increases of NO synthase production, suggesting that NO is a vasoactive mediator of CBF.     

Sex-specific differences in cerebral arterial myogenic tone in hypertensive and normotensive rats

Cerebral blood flow (CBF) is maintained constant despite changes in systemic blood pressure (BP) through multiple mechanisms of autoregulation such as vascular myogenic reactivity. Our aim was to determine myogenic characteristics of cannulated middle cerebral arteries (MCA) in male and female stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto rats (WKY) at 12 wk of age under pressurised no-flow conditions. MCA pressure-diameter relationships (20-200 mmHg) were constructed in active (with calcium) and passive (without calcium) conditions, and myogenic and mechanical properties were determined. Myogenic reactivity in WKY (P < 0.05) and SHRSP (P < 0.05) males was impaired compared with their female counterparts. Comparison of SHRSP with WKY in males revealed similar myogenic reactivity, but in females SHRSP exhibited augmented myogenic reactivity (P < 0.05). In both sexes, myogenic tone yielded at lower pressure in SHRSP compared with WKY vessels (120-140 vs. 140-180 mmHg). Stress-strain relationships and elastic moduli in WKY rats showed that vessels were stiffer in females than in males. Conversely, in SHRSP, male vessels were stiffer than female vessels. Comparison of strains in males indicated that stiffness was increased in SHRSP compared with WKY vessels, whereas the converse was observed in females. These findings demonstrate that MCA myogenic and distensibility characteristics exhibit significant sex- and strain-dependent differences. Inappropriate myogenic adaptation and augmented vascular stiffness, particularly in male SHRSP, are potential limiting factors in blood flow autoregulation and may increase the predisposition for stroke-related cerebrovascular events.     

Two-breath CO(2) test detects altered dynamic cerebrovascular autoregulation and CO(2) responsiveness with changes in arterial P(CO(2))

The new two-breath CO(2) method was employed to test the hypotheses that small alterations in arterial P(CO(2)) had an impact on the magnitude and dynamic response time of the CO(2) effect on cerebrovascular resistance (CVRi) and the dynamic autoregulatory response to fluctuations in arterial pressure. During a 10-min protocol, eight subjects inspired two breaths from a bag with elevated P(CO(2)), four different times, while end-tidal P(CO(2)) was maintained at three levels: hypocapnia (LoCO(2), 8 mmHg below resting values), normocapnia, and hypercapnia (HiCO(2), 8 mmHg above resting values). Continuous measurements were made of mean blood pressure corrected to the level of the middle cerebral artery (BP(MCA)), P(CO(2)) (estimated from expired CO(2)), and mean flow velocity (MFV, of the middle cerebral artery by Doppler ultrasound), with CVRi = BP(MCA)/MFV. Data were processed by a system identification technique (autoregressive moving average analysis) with gain and dynamic response time of adaptation estimated from the theoretical step responses. Consistent with our hypotheses, the magnitude of the P(CO(2))-CVRi response was reduced from LoCO(2) to HiCO(2) [from -0.04 (SD 0.02) to -0.01 (SD 0.01) (mmHg x cm(-1) x s) x mmHg Pco(2)(-1)] and the time to reach 95% of the step plateau increased from 12.0 +/- 4.9 to 20.5 +/- 10.6 s. Dynamic autoregulation was impaired with elevated P(CO(2)), as indicated by a reduction in gain from LoCO(2) to HiCO(2) [from 0.021 +/- 0.012 to 0.007 +/- 0.004 (mmHg x cm(-1) x s) x mmHg BP(MCA)(-1)], and time to reach 95% increased from 3.7 +/- 2.8 to 20.0 +/- 9.6 s. The two-breath technique detected dependence of the cerebrovascular CO(2) response on P(CO(2)) and changes in dynamic autoregulation with only small deviations in estimated arterial P(CO(2)).     

Cerebrovascular reserve in the cat after acute bilateral carotid occlusion

Cerebral blood flow in the cat was studied before and after acute bilateral common carotid occlusion under normocapnic and hypercapnic conditions and after induced hypotension. Regional blood flow to different brain structures was studied with the microsphere method. Local blood flow in the caudate nucleus, the cerebral cortex and medulla oblongata was studied with H2-polarography. Although the blood flow to the anterior brain regions is significantly decreased after bilateral common carotid occlusion, their blood supply is kept above ischaemic levels by re-distribution of the vertebrobasilar flow. Cerebrovascular reserve in anterior brain regions, however, is lost as indicated by the severe impairment of both the flow response to hypercapnia and to blood pressure decrease. After bilateral common carotid occlusion paradoxical CO2-reactions, indicating intracerebral steal, were seen in the caudate nucleus. In posterior brain regions resting blood flow, flow-reaction to hypercapnia and to hypotension are better preserved under these conditions. Measurement of the CBF responses to induced hypercapnia is a dependable test for appreciation of cerebrovascular reserve after cerebrovascular occlusion but may be potentially hazardous where local flow is close to ischaemic levels.     

Assessing Cerebral Autoregulation via Oscillatory Lower Body Negative Pressure and Projection Pursuit Regression

The process by which cerebral perfusion is maintained constant over a wide range of systemic pressures is known as “cerebral autoregulation.” Effective dampening of flow against pressure changes occurs over periods as short as ~15 sec and becomes progressively greater over longer time periods. Thus, slower changes in blood pressure are effectively blunted and faster changes or fluctuations pass through to cerebral blood flow relatively unaffected. The primary difficulty in characterizing the frequency dependence of cerebral autoregulation is the lack of prominent spontaneous fluctuations in arterial pressure around the frequencies of interest (less than ~0.07 Hz or ~15 sec). Oscillatory lower body negative pressure (OLBNP) can be employed to generate oscillations in central venous return that result in arterial pressure fluctuations at the frequency of OLBNP. Moreover, Projection Pursuit Regression (PPR) provides a nonparametric method to characterize nonlinear relations inherent in the system without a priori assumptions and reveals the characteristic non-linearity of cerebral autoregulation. OLBNP generates larger fluctuations in arterial pressure as the frequency of negative pressure oscillations become slower; however, fluctuations in cerebral blood flow become progressively lesser. Hence, the PPR shows an increasingly more prominent autoregulatory region at OLBNP frequencies of 0.05 Hz and below (20 sec cycles). The goal of this approach it to allow laboratory-based determination of the characteristic nonlinear relationship between pressure and cerebral flow and could provide unique insight to integrated cerebrovascular control as well as to physiological alterations underlying impaired cerebral autoregulation (e.g., after traumatic brain injury, stroke, etc.).     

Cerebral hemodynamics during orthostatic stress assessed by nonlinear modeling.

The effects of orthostatic stress, induced by lower body negative pressure (LBNP), on cerebral hemodynamics were examined in a nonlinear context. Spontaneous fluctuations of beat-to-beat mean arterial blood pressure (MABP) in the finger, mean cerebral blood flow velocity (MCBFV) in the middle cerebral artery, as well as breath-by-breath end-tidal CO2 concentration (P(ET(CO2))) were measured continuously in 10 healthy subjects under resting conditions and during graded LBNP to presyncope. A two-input nonlinear Laguerre-Volterra network model was employed to study the dynamic effects of MABP and P(ET(CO2)) changes, as well as their nonlinear interactions, on MCBFV variations in the very low (VLF; below 0.04 Hz), low (LF; 0.04-0.15 Hz), and high frequency (HF; 0.15-0.30 Hz) ranges. Dynamic cerebral autoregulation was described by the model terms corresponding to MABP, whereas cerebral vasomotor reactivity was described by the model P(ET(CO2)) terms. The nonlinear model terms reduced the output prediction normalized mean square error substantially (by 15-20%) and had a prominent effect in the VLF range, both under resting conditions and during LBNP. Whereas MABP fluctuations dominated in the HF range and played a significant role in the VLF and LF ranges, changes in P(ET(CO2)) accounted for a considerable fraction of the VLF and LF MCBFV variations, especially at high LBNP levels. The magnitude of the linear and nonlinear MABP-MCBFV Volterra kernels increased substantially above -30 mmHg LBNP in the VLF range, implying impaired dynamic autoregulation. In contrast, the magnitude of the P(ET(CO2))-MCBFV kernels reduced during LBNP at all frequencies, suggesting attenuated cerebral vasomotor reactivity under dynamic conditions. We speculate that these changes may reflect a progressively reduced cerebrovascular reserve to compensate for the increasingly unstable systemic circulation during orthostatic stress that could ultimately lead to cerebral hypoperfusion and syncope.     

Cerebrovascular responsiveness to steady-state changes in end-tidal CO2 during passive heat stress.

This study tested the hypothesis that passive heat stress alters cerebrovascular responsiveness to steady-state changes in end-tidal CO(2) (Pet(CO(2))). Nine healthy subjects (4 men and 5 women), each dressed in a water-perfused suit, underwent normoxic hypocapnic hyperventilation (decrease Pet(CO(2)) approximately 20 Torr) and normoxic hypercapnic (increase in Pet(CO(2)) approximately 9 Torr) challenges under normothermic and passive heat stress conditions. The slope of the relationship between calculated cerebrovascular conductance (CBVC; middle cerebral artery blood velocity/mean arterial blood pressure) and Pet(CO(2)) was used to evaluate cerebrovascular CO(2) responsiveness. Passive heat stress increased core temperature (1.1 +/- 0.2 degrees C, P < 0.001) and reduced middle cerebral artery blood velocity by 8 +/- 8 cm/s (P = 0.01), reduced CBVC by 0.09 +/- 0.09 CBVC units (P = 0.02), and decreased Pet(CO(2)) by 3 +/- 4 Torr (P = 0.07), while mean arterial blood pressure was well maintained (P = 0.36). The slope of the CBVC-Pet(CO(2)) relationship to the hypocapnic challenge was not different between normothermia and heat stress conditions (0.009 +/- 0.006 vs. 0.009 +/- 0.004 CBVC units/Torr, P = 0.63). Similarly, in response to the hypercapnic challenge, the slope of the CBVC-Pet(CO(2)) relationship was not different between normothermia and heat stress conditions (0.028 +/- 0.020 vs. 0.023 +/- 0.008 CBVC units/Torr, P = 0.31). These results indicate that cerebrovascular CO(2) responsiveness, to the prescribed steady-state changes in Pet(CO(2)), is unchanged during passive heat stress.