A multiscale 0-D/3-D approach to patient-specific adaptation of a cerebral autoregulation model for computational fluid dynamics studies of cardiopulmonary bypass

Neurological complication often occurs during cardiopulmonary bypass (CPB). One of the main causes is hypoperfusion of the cerebral tissue affected by the position of the cannula tip and diminished cerebral autoregulation (CA). Recently, a lumped parameter approach could describe the baroreflex, one of the main mechanisms of cerebral autoregulation, in a computational fluid dynamics (CFD) study of CPB. However, the cerebral blood flow (CBF) was overestimated and the physiological meaning of the variables and their impact on the model was unknown. In this study, we use a 0-D control circuit representation of the Baroreflex mechanism, to assess the parameters with respect to their physiological meaning and their influence on CBF. Afterwards the parameters are transferred to 3D-CFD and the static and dynamic behavior of cerebral autoregulation is investigated.     

A simple mathematical model of the interaction between intracranial pressure and cerebral hemodynamics

Ursino, Mauro, and Carlo Alberto Lodi. A simplemathematical model of the interaction between intracranial pressure andcerebral hemodynamics. J. Appl.Physiol. 82(4): 1256-1269, 1997.A simplemathematical model of intracranial pressure (ICP) dynamics oriented toclinical practice is presented. It includes the hemodynamics of thearterial-arteriolar cerebrovascular bed, cerebrospinal fluid (CSF)production and reabsorption processes, the nonlinear pressure-volumerelationship of the craniospinal compartment, and a Starling resistormechanism for the cerebral veins. Moreover, arterioles are controlledby cerebral autoregulation mechanisms, which are simulated by means ofa time constant and a sigmoidal static characteristic. The model isused to simulate interactions between ICP, cerebral blood volume, andautoregulation. Three different related phenomena are analyzed: thegeneration of plateau waves, the effect of acute arterial hypotensionon ICP, and the role of cerebral hemodynamics during pressure-volume index (PVI) tests. Simulation results suggest the following:1) ICP dynamics may become unstablein patients with elevated CSF outflow resistance and decreasedintracranial compliance, provided cerebral autoregulation is efficient.Instability manifests itself with the occurrence of self-sustainedplateau waves. 2) Moderate acutearterial hypotension may have completely different effects on ICP,depending on the value of model parameters. If physiological compensatory mechanisms (CSF circulation and intracranial storage capacity) are efficient, acute hypotension has only negligible effectson ICP and cerebral blood flow (CBF). If these compensatory mechanismsare poor, even modest hypotension may induce a large transient increasein ICP and a significant transient reduction in CBF, with risks ofsecondary brain damage. 3) The ICPresponse to a bolus injection (PVI test) is sharply affected, viacerebral blood volume changes, by cerebral hemodynamics andautoregulation. We suggest that PVI tests may be used to extractinformation not only on intracranial compliance and CSF circulation,but also on the status of mechanisms controlling CBF.

     

A model of the interaction between autoregulation and neural activation in the brain

In this paper a model is proposed that predicts the response of the cerebral vasculature to changes in arterial blood pressure, arterial CO2 concentration and neural stimulation. Cerebral blood flow (CBF) is assumed to be controlled through changes in arterial compliance, and hence arterial resistance and volume, through three feedback mechanisms, which act in a linear additive manner, based on CBF, arterial CO2 and neural stimulus. Together with arterial, capillary and venous compartments, a tissue compartment is included, which contributes partly to the initial rise found in the deoxyhaemoglobin response to neural activation. Dynamic simulations of the model under different conditions show that there is significant interaction between the autoregulation and activation processes, and that the level of autoregulation has a strong influence on the CBF and deoxyhaemoglobin responses to neural activation. Overshoot in the deoxyhaemoglobin response is eliminated completely in the absence of this regulation. The feedback mechanism time constants significantly affect the CBF and deoxyhaemoglobin responses. Changes in arterial blood pressure (ABP) are found to have a strong influence on the neural activation response, with the amplitude of the response decreasing significantly at high baseline ABP. Dynamic changes in ABP also have a significant and potentially confounding impact on the measured deoxyhaemoglobin response to neural activation.     

Cerebrovascular autoregulation is profoundly impaired in mice overexpressing amyloid precursor protein

The amyloid-beta (A beta) peptide, which is derived from the amyloid precursor protein (APP), is involved in the pathogenesis of Alzheimer's dementia and impairs endothelium-dependent vasodilation in cerebral vessels. We investigated whether cerebrovascular autoregulation, i.e., the ability of the cerebral circulation to maintain flow in the face of changes in mean arterial pressure (MAP), is impaired in transgenic mice that overexpress APP and A beta. Neocortical cerebral blood flow (CBF) was monitored by laser-Doppler flowmetry in anesthetized APP(+) and APP(-) mice. MAP was elevated by intravenous infusion of phenylephrine and reduced by controlled exsanguination. In APP(-) mice, autoregulation was preserved. However, in APP(+) mice, autoregulation was markedly disrupted. The magnitude of the disruption was linearly related to brain A beta concentration. The failure of autoregulation was paralleled by impairment of the CBF response to endothelium-dependent vasodilators. Thus A beta disrupts a critical homeostatic mechanism of the cerebral circulation and renders CBF highly dependent on MAP. The resulting alterations in cerebral perfusion may play a role in the brain dysfunction and periventricular white-matter changes associated with Alzheimer's dementia.     

A global mathematical model of the cerebral circulation in man

A mathematical model of the cerebral circulation has been formulated. It was based on non-linear equations of pulsatile fluid flow in distensible conduits and applied to a network simulating the entire cerebral vasculature, from the carotid and vertebral arteries to the sinuses and the jugular veins. The quasilinear hyperbolic system of equations was numerically solved using the two-step Lax-Wendroff scheme. The model's results were in good agreement with pressure and flow data recorded in humans during rest. The model was also applied to the study of autoregulation during arterial hypotension. A close relationship between cerebral blood flow (CBF) and capillary pressure was obtained. At arterial pressure of 80 mmHg, the vasodilation of the pial arteries was unable to maintain CBF at its control value. At the lower limit of autoregulation (60 mm Hg), CBF was maintained with a 25% increase of zero transmural pressure diameter of nearly the whole arterial network.     

Cerebral blood flow autoregulation in early experimental S. pneumoniae meningitis.

We studied cerebral blood flow (CBF) autoregulation and intracranial pressure (ICP) during normo- and hyperventilation in a rat model of Streptococcus pneumoniae meningitis. Meningitis was induced by intracisternal injection of S. pneumoniae. Mean arterial blood pressure (MAP), ICP, cerebral perfusion pressure (CPP, defined as MAP - ICP), and laser-Doppler CBF were measured in anesthetized infected rats (n = 30) and saline-inoculated controls (n = 30). CPP was either incrementally reduced by controlled hemorrhage or increased by intravenous norepinephrine infusion. Twelve hours postinoculation, rats were studied solely during normocapnia, whereas rats studied after 24 h were exposed to either normocapnia or to acute hypocapnia. In infected rats compared with control rats, ICP was unchanged at 12 h but increased at 24 h postinoculation (not significant and P < 0.01, respectively); hypocapnia did not lower ICP compared with normocapnia. Twelve hours postinoculation, CBF autoregulation was lost in all infected rats but preserved in all control rats (P < 0.01). Twenty-four hours after inoculation, 10% of infected rats had preserved CBF autoregulation during normocapnia compared with 80% of control rats (P < 0.01). In contrast, 60% of the infected rats and 100% of the control rats showed an intact CBF autoregulation during hypocapnia (P < 0.05 for the comparison of infected rats at normocapnia vs. hypocapnia). In conclusion, CBF autoregulation is lost both at 12 and at 24 h after intracisternal inoculation of S. pneumoniae in rats. Impairment of CBF autoregulation precedes the increase in ICP, and acute hypocapnia may restore autoregulation without changing the ICP.     

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.     

Dynamic cardiorespiratory interaction during head-up tilt-mediated presyncope

In 28 healthy adults, we compared the dynamic interaction between respiration and cerebral autoregulation in 2 groups of subjects: those who did and did not develop presyncopal symptoms during 70 degrees passive head-up tilt (HUT), i.e., nonpresyncopal (23 subjects) and presyncopal (5 subjects). Airflow, CO2, cerebral blood flow velocity (CBF), ECG, and blood pressure (BP) were recorded. To determine whether influences of mean BP (MBP) and systolic SP (SBP) on CBF were altered in presyncopal subjects, coherencies and transfer functions between these variables and mean and peak CBF (CBFm and CBFp) were estimated. To determine the influence of end-tidal CO2 (ETco2) on CBF, the relative CO2 reactivity (%change in CBFm per mmHg change in ETco2) was calculated. We found that in presyncopal subjects before symptoms during HUT, coherence between SBP and CBFp was higher (P=0.02) and gains of transfer functions between BP (MBP and SBP) and CBFm were larger (MBP, P=0.01; SBP, P=0.01) in the respiratory frequency region. In the last 3 min before presyncope, presyncopals had a reduced relative CO2 reactivity (P=0.005), likely a consequence of the larger decrease in ETco2. We hypothesize that the CO2-mediated increase in resistance attenuates autoregulation such that the relationship between systemic and cerebral hemodynamics is enhanced. Our results suggest that an altered cardiorespiratory interaction involving cerebral hemodynamics may contribute in the cascade of events during tilt that culminate in unexplained syncope.     

Blood pressure and blood flow variation during postural change from sitting to standing: model development and validation.

Short-term cardiovascular responses to postural change from sitting to standing involve complex interactions between the autonomic nervous system, which regulates blood pressure, and cerebral autoregulation, which maintains cerebral perfusion. We present a mathematical model that can predict dynamic changes in beat-to-beat arterial blood pressure and middle cerebral artery blood flow velocity during postural change from sitting to standing. Our cardiovascular model utilizes 11 compartments to describe blood pressure, blood flow, compliance, and resistance in the heart and systemic circulation. To include dynamics due to the pulsatile nature of blood pressure and blood flow, resistances in the large systemic arteries are modeled using nonlinear functions of pressure. A physiologically based submodel is used to describe effects of gravity on venous blood pooling during postural change. Two types of control mechanisms are included: 1) autonomic regulation mediated by sympathetic and parasympathetic responses, which affect heart rate, cardiac contractility, resistance, and compliance, and 2) autoregulation mediated by responses to local changes in myogenic tone, metabolic demand, and CO(2) concentration, which affect cerebrovascular resistance. Finally, we formulate an inverse least-squares problem to estimate parameters and demonstrate that our mathematical model is in agreement with physiological data from a young subject during postural change from sitting to standing.     

Inhibition of nitric oxide synthase does not alter dynamic cerebral autoregulation in humans

The aim of this study was to determine whether inhibition of nitric oxide synthase (NOS) alters dynamic cerebral autoregulation in humans. Beat-to-beat blood pressure (BP) and cerebral blood flow (CBF) velocity (transcranial Doppler) were measured in eight healthy subjects in the supine position and during 60 degrees head-up tilt (HUT). NOS was inhibited by intravenous NG-monomethyl-L-arginine (L-NMMA) infusion. Dynamic cerebral autoregulation was quantified by transfer function analysis of beat-to-beat changes in BP and CBF velocity. Pressor effects of L-NMMA on cerebral hemodynamics were compared with those of phenylephrine infusion. In the supine position, L-NMMA increased mean BP from 83+/-3 to 94+/-3 mmHg (P < 0.01). However, CBF velocity remained unchanged. Consequently, cerebrovascular resistance index (CVRI) increased by 15% (P < 0.05). BP and CBF velocity variability and transfer function gain at the low frequencies of 0.07-0.20 Hz did not change with L-NMMA infusion. Similar changes in mean BP, CBF velocity, and CVRI were observed after phenylephrine infusion, suggesting that increase in CVRI after L-NMMA was mediated myogenically by increase in arterial pressure rather than a direct effect of cerebrovascular NOS inhibition. During baseline tilt without L-NMMA, steady-state BP increased and CBF velocity decreased. BP and CBF velocity variability at low frequencies increased in parallel by 277% and 217%, respectively (P < 0.05). However, transfer function gain remained unchanged. During tilt with L-NMMA, changes in steady-state hemodynamics and BP and CBF velocity variability as well as transfer gain and phase were similar to those without L-NMMA. These data suggest that inhibition of tonic production of NO does not appear to alter dynamic cerebral autoregulation in humans.     

Cerebral white matter blood flow is constant during human non-rapid eye movement sleep: a positron emission tomographic study.

This study aimed to identify brain regions with the least decreased cerebral blood flow (CBF) and their relationship to physiological parameters during human non-rapid eye movement (NREM) sleep. Using [(15)O]H(2)O positron emission tomography, CBF was measured for nine normal young adults during nighttime. As NREM sleep progressed, mean arterial blood pressure and whole brain mean CBF decreased significantly; arterial partial pressure of CO(2) and, selectively, relative CBF of the cerebral white matter increased significantly. Absolute CBF remained constant in the cerebral white matter, registering 25.9 +/- 3.8 during wakefulness, 25.8 +/- 3.3 during light NREM sleep, and 26.9 +/- 3.0 (ml.100 g(-1).min(-1)) during deep NREM sleep (P = 0.592), and in the occipital cortex (P = 0.611). The regression slope of the absolute CBF significantly differed with respect to arterial partial pressure of CO(2) between the cerebral white matter (slope 0.054, R = - 0.04) and frontoparietal association cortex (slope - 0.776, R = - 0.31) (P = 0.005) or thalamus (slope - 1.933, R = - 0.47) (P = 0.004) and between the occipital cortex (slope 0.084, R = 0.06) and frontoparietal association cortex (P = 0.021) or thalamus (P < 0.001), and, with respect to mean arterial blood pressure, between the cerebral white matter (slope - 0.067, R = - 0.10) and thalamus (slope 0.637, R = 0.31) (P = 0.044). The cerebral white matter CBF keeps constant during NREM sleep as well as the occipital cortical CBF, and may be specifically regulated by both CO(2) vasoreactivity and pressure autoregulation.     

Metabolic model of autoregulation in the Circle of Willis

The Circle of Willis (CoW) is a ringlike structure of blood vessels found at the base of the brain. Its main function is to distribute oxygen-rich arterial blood to the cerebral mass. In a previous study, a one-dimensional (1D) model of the CoW was created to simulate a series of possible clinical scenarios such as occlusions in afferent arteries, absent or stringlike circulus vessels, or arterial infarctions (Moorhead et al., 2004, Comput. Methods Biomech. Biomed. Eng., 7(3), pp. 121-130). The model captured cerebral haemodynamic autoregulation by using a proportional-integral-derivative (PID) controller to modify efferent artery resistances. Although some good results and correlations were achieved, the model was too simple to capture all the transient dynamics of autoregulation. Hence a more physiologically accurate model has been created that additionally includes the oxygen dynamics that drive the autoregulatory response. Results very closely match accepted physiological response and limited clinical data. In addition, a set of boundary conditions and geometry is presented for which the autoregulated system cannot provide sufficient perfusion, representing a condition with increased risk of stroke and highlighting the importance of modeling the haemodynamics of the CoW. The system model created is computationally simple so it can be used to identify at-risk cerebral arterial geometries and conditions prior to surgery or other clinical procedures.     

Cerebral circulation during mild +Gz hypergravity by short-arm human centrifuge

We examined changes in cerebral circulation in 15 healthy men during exposure to mild +Gz hypergravity (1.5 Gz, head-to-foot) using a short-arm centrifuge. Continuous arterial pressure waveform (tonometry), cerebral blood flow (CBF) velocity in the middle cerebral artery (transcranial Doppler ultrasonography), and partial pressure of end-tidal carbon dioxide (ETco(2)) were measured in the sitting position (1 Gz) and during 21 min of exposure to mild hypergravity (1.5 Gz). Dynamic cerebral autoregulation was assessed by spectral and transfer function analysis between beat-to-beat mean arterial pressure (MAP) and mean CBF velocity (MCBFV). Steady-state MAP did not change, but MCBFV was significantly reduced with 1.5 Gz (-7%). ETco(2) was also reduced (-12%). Variability of MAP increased significantly with 1.5 Gz in low (53%)- and high-frequency ranges (88%), but variability of MCBFV did not change in these frequency ranges, resulting in significant decreases in transfer function gain between MAP and MCBFV (gain in low-frequency range, -17%; gain in high-frequency range, -13%). In contrast, all of these indexes in the very low-frequency range were unchanged. Transfer from arterial pressure oscillations to CBF fluctuations was thus suppressed in low- and high-frequency ranges. These results suggest that steady-state global CBF was reduced, but dynamic cerebral autoregulation in low- and high-frequency ranges was improved with stabilization of CBF fluctuations despite increases in arterial pressure oscillations during mild +Gz hypergravity. We speculate that this improvement in dynamic cerebral autoregulation within these frequency ranges may have been due to compensatory effects against the reduction in steady-state global CBF.     

Critical closing pressure explains cerebral hemodynamics during the Valsalva maneuver

The Valsalvamaneuver (VM), a voluntary increase in intrathoracic pressure of ~40mmHg, has been used to examine cerebral autoregulation (CA). Duringphase IV of the VM there are pronounced changes in mean arterial bloodpressure (MABP), pulse interval, and cerebral blood flow (CBF), but thechanges in CBF are of a much greater magnitude than those seen in MABP,a finding to date attributed to either a delay in activation of the CAmechanism or the inability of this mechanism to cope with the size andspeed of the blood pressure changes involved. These changes in CBF also precede those in MABP, a pattern of events not explained by the physiological process of CA. Measurements of CBF velocity (transcranial Doppler) and MABP (Finapres) were performed in 53 healthy volunteers (aged 31-80 yr). By calculating beat-to-beat values of critical closing pressure (CCP) during the VM, we have found that this parametersuddenly drops at the start of phase IV, providing a coherentexplanation for the large increase in CBF. If CCP is included in theestimation of cerebrovascular resistance, a temporal pattern moreconsistent with an autoregulatory response to the MABP overshoot isalso found. CCP is intricately involved in the control of CBF duringthe VM and should be considered in the assessment of CA.     

Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease.

The brain is critically dependent on a continuous supply of blood to function. Therefore, the cerebral vasculature is endowed with neurovascular control mechanisms that assure that the blood supply of the brain is commensurate to the energy needs of its cellular constituents. The regulation of cerebral blood flow (CBF) during brain activity involves the coordinated interaction of neurons, glia, and vascular cells. Thus, whereas neurons and glia generate the signals initiating the vasodilation, endothelial cells, pericytes, and smooth muscle cells act in concert to transduce these signals into carefully orchestrated vascular changes that lead to CBF increases focused to the activated area and temporally linked to the period of activation. Neurovascular coupling is disrupted in pathological conditions, such as hypertension, Alzheimer disease, and ischemic stroke. Consequently, CBF is no longer matched to the metabolic requirements of the tissue. This cerebrovascular dysregulation is mediated in large part by the deleterious action of reactive oxygen species on cerebral blood vessels. A major source of cerebral vascular radicals in models of hypertension and Alzheimer disease is the enzyme NADPH oxidase. These findings, collectively, highlight the importance of neurovascular coupling to the health of the normal brain and suggest a therapeutic target for improving brain function in pathologies associated with cerebrovascular dysfunction.     

Effect of nephrectomy and captopril on autoregulation of cerebral blood flow in rats

The present study investigated the effect of circulating versus locally present renin on cerebral blood flow (CBF) and its autoregulation in rats. CBF was measured repetitively with the intracarotid 133Xe injection method, whereas blood pressure was lowered to determine the lower limit of autoregulation. To remove renin from the blood, rats were bilaterally nephrectomized and kept alive with peritoneal dialysis for 48 h. Five groups of animals were studied: 1) nephrectomized dialyzed rats, 2) nephrectomized dialyzed rats given a single intravenous dose of the angiotensin-converting enzyme inhibitor captopril (10 mg/kg), 3) sham nephrectomized and dialyzed rats, 4) rats receiving drugs as dialyzed rats but no surgery, and 5) rats given the same diet as the other groups but no drugs and no surgery. Baseline blood pressure was significantly lower in nephrectomized rats compared with controls. Nephrectomy, captopril, sham operation, or dialysis did not influence baseline CBF. The lower limit of CBF autoregulation was significantly lower in nephrectomized (53 +/- 4 mmHg) and sham-operated (58 +/- 4 mmHg) rats compared with diet control rats (78 +/- 3 mmHg). Captopril significantly decreased the lower limit in nephrectomized rats (35 +/- 2 mmHg). Thus removal of circulating renin caused no change in the lower limit of autoregulation. By contrast, captopril lowered the lower limit even in the absence of circulating renin and hence appeared to exert its effect on components of the renin-angiotensin system in the cerebral resistance vessel walls.     

Noninvasive Optical Measurement of Cerebral Blood Flow in Mice Using Molecular Dynamics Analysis of Indocyanine Green

In preclinical studies of ischemic brain disorders, it is crucial to measure cerebral blood flow (CBF); however, this requires radiological techniques with heavy instrumentation or invasive procedures. Here, we propose a noninvasive and easy-to-use optical imaging technique for measuring CBF in experimental small animals. Mice were injected with indocyanine green (ICG) via tail-vein catheterization. Time-series near-infrared fluorescence signals excited by 760 nm light-emitting diodes were imaged overhead by a charge-coupled device coupled with an 830 nm bandpass-filter. We calculated four CBF parameters including arrival time, rising time and mean transit time of a bolus and blood flow index based on time and intensity information of ICG fluorescence dynamics. CBF maps were generated using the parameters to estimate the status of CBF, and they dominantly represented intracerebral blood flows in mice even in the presence of an intact skull and scalp. We demonstrated that this noninvasive optical imaging technique successfully detected reduced local CBF during middle cerebral artery occlusion. We further showed that the proposed method is sufficiently sensitive to detect the differences between CBF status in mice anesthetized with either isoflurane or ketamine–xylazine, and monitor the dynamic changes in CBF after reperfusion during transient middle cerebral artery occlusion. The near-infrared optical imaging of ICG fluorescence combined with a time-series analysis of the molecular dynamics can be a useful noninvasive tool for preclinical studies of brain ischemia.     

Gene transfer of Cu/Zn SOD to cerebral vessels prevents FPI-induced CBF autoregulatory dysfunction

The goal of this study was to determine whether gene transfer of human copper-zinc (Cu/Zn) superoxide dismutase (SOD) has preventive effects on cerebral blood flow (CBF) autoregulatory dysfunction after fluid percussion injury (FPI). Rats subjected to FPI (2-2.5 atm) exhibited enhanced activity of reduced NADP (NADPH) oxidase in the cerebral vasculature. In line with these findings, the rats showed not only reduced vasodilation of the pial artery in response to calcitonin gene-related peptide and levcromakalim but also impaired autoregulatory vasodilation in response to acute hypotension. The FPI-induced hemodynamic alterations were significantly prevented by pretreatment with diphenyleneiodonium (10 micromol/l), an NAD(P)H oxidase inhibitor. Intracisternal application of recombinant adenovirus (100 microl of 1 x 10(10) pfu/ml)-encoding human Cu/Zn SOD 3 days before FPI prevented the impairment of vasodilation to hypotension and vasorelaxants, resulting in the restoration of CBF autoregulation. Our findings demonstrate that FPI-induced impairment of CBF autoregulation is closely related with NAD(P)H oxidase-derived superoxide anion, and these alterations can be prevented by the recombinant adenovirus-mediated transfer of human Cu/Zn SOD gene to the cerebral vasculature.     

Effect of hypothermia on brain multi-parametric activities in normoxic and partially ischemic rats

Hypothermia, as well as anesthesia, are known to protect the brain against ischemia, hypoxia and other pathological damages. One of the mechanisms of this improvement could be by lowering brain function, and thereby lowering oxygen demand. We examined the effect of hypothermia on brain function and blood supply in awake and anesthetized rats and studied the interaction between partial ischemia and the responses to hypothermia. The brain function multiprobe (BFM) used enabled simultaneous measurements of cerebral blood flow (CBF), mitochondrial NADH redox state, extracellular K(+) concentration, DC potential and ECoG from the cerebral cortex in rats whose brain temperature was lowered by 5 degrees C. Hypothermia was induced in awake, anesthetized and brain ischemic-anesthetized rats. In anesthetized and ischemic-anesthetized rats, the time required for lowering the brain temperature by 5 degrees C was five times less than in the normal awake animals. No significant changes in CBF and NADH levels were found in response to hypothermia in the awake animals. In contrast, a significant decrease in extracellular K(+) concentration was recorded under hypothermia, probably due to the lower rate of depolarization. Hypothermia in anesthetized and in ischemic-anesthetized rats did not significantly affect the levels of mitochondrial NADH, CBF and extracellular K(+). Hypothermia under ischemia was expected to be more effective.     

Effects of combination alfaxalone and alfadolone, anesthetic derivatives of pregnanedione, on cerebral hemodynamics in cats]

Intravenous injection of CT 1341 (a mixture of alphaxalone and alphadolone dissolved in cremophor el) induced a decrease in cerebral blood flow (CBF) measured by 133Xe clearance in cats with artificial respiration (the mean reduction in CBF was 2 ml/100 g/mn for 1,2 mg/kg or CT 1341. So, CBF was decreased by 22% when CT 1341 (7,2 mg/kg) was intravenously injected, (mean Pa CO2 equals 30 mm Hg). Changes in CBF following CT 1341 intravenous injection seems to be caused by cerebral vascular constriction evidenced by the direct observation of pial vessels. Following intravenous injection of CT 1341 (from 7, 2 mg/kg to 19,2 mg/kg), the cerebrovascular reactivity to hypercapnia or hypocapnia was not affected, but autoregulation of cerebral blood flow was transiently abolished. In animals with free respiration, CBF was increased in relation with the elevation in Pa CO2 caused by the depression of respiration.