Cerebral Blood Flow and Vascular Physiology

Cerebral Blood Flow and Vascular Physiology

Paper Outline:

Cerebrovascular anatomy
Arterial supply
Venous drainage
Dural venous sinuses
Normal cerebral blood flow and metabolism
Measurement of cerebral blood flow
Global CBF
Regional CBF
Transcranial Doppler sonography
Local CBF
Control of the cerebral circulation
Flow–metabolism coupling
Mediators of flow–metabolism coupling
Temperature effects on flow–metabolism coupling
CO2 vasoreactivity
Mechanism of CO2 vasoreactivity
Conditions that alter CO2 vasoreactivity
Hypoxemia-induced cerebral vasodilation
Effects of viscosity on CBF
Blood pressure or cerebral perfusion pressure (cerebral autoregulation)
Normal flow, pressure, and resistance relationships
Mechanisms of autoregulation
The metabolic mechanism
The myogenic mechanism
The neurogenic mechanism
Abnormal autoregulation
Limits of autoregulation
Autoregulation testing
Conclusion
Appendix
References
Copyright

Cerebrovascular anatomy

Arterial supply
The two common carotid arteries (anterior circulation) and the two vertebral arteries (posterior circulation) supply blood to the anterior and posterior parts of the brain respectively. In general (65–70% of patients), the common carotid arteries originate from the innominate artery on the right side and from the aorta on the left side. In adults, bifurcation of the common carotid artery into the internal and external carotid arteries occurs usually at C4,5 compared to children in whom bifurcation occurs one to two cervical levels rostral [1]. The internal carotid artery (ICA) supplies the brain and the ipsilateral eye. There are four segments of the ICA: cervical, petrous, cavernous, and supraclinoid, describing its course as it enters the cranium. In general, the size of the area supplied by the artery determines the diameter of the cerebral artery [2]. The ophthalmic, posterior communicating, anterior choroidal, anterior cerebral, middle cerebral, and anterior perforating arteries are all branches of the ICA, and provide most of the blood supply to the cerebrum. All areas of the brain supplied by the main branches of the ICA have good collateral circulation except the area supplied by the middle cerebral artery (MCA). As a result, the MCA territory is prone to ischemia.

The two vertebral arteries and the basilar artery comprise the posterior circulation. The vertebral arteries are the largest branches of the subclavian artery, and before merging to form the basilar artery, the verterbral arteries give rise to the anterior spinal and posterior inferior cerebellar arteries. Each anterior spinal ramus originating from the vertebral artery merges with the opposite spinal ramus to form the anterior spinal artery. The posterior inferior cerebellar artery is the largest branch of the vertebral artery, and supplies the cerebellum and lower brainstem. The basilar artery ascends ventral to the pons and terminates in the pontomesencephalic junction. It gives rise to the anterior inferior cerebellar, superior cerebellar, and posterior cerebral arteries. The posterior communicating arteries (Pcom) connect the basilar artery to the carotid circulation.

The Circle of Willis represents an anastomosis of the basal cerebral arteries and the potential collateral circulation. This polygonal-shaped ring is composed of the anterior communicating segments (Acom) of the anterior cerebral artery, and the ICA anteriorly. The posterior portion of the circle of Willis is composed of the two Pcoms, and the two posterior cerebral arteries. However, this classic pattern is found in less than 50% of the people; the Acom and Pcom are frequently hypoplastic. While the main function of the Circle of Willis is to provide collateral flow to the part of the brain with insufficient blood flow, hypoplasia of the Acom or Pcom can be a limiting factor.

Venous drainage

The venous system of the brain consists of superficial and deep cerebral veins. The superficial veins drain from the surface and the cortex of the cerebral hemispheres, whereas the deep veins drain from the deep white matter, the basal ganglia, the diencephalons, the cerebellum, and the brainstem. Large subependymal veins empty into the basal veins to form the great vein of Galen, which is part of the deep venous system. Both superficial and deep veins including the vein of Galen drain into the major dural venous sinuses, which, in addition to receiving blood from the brain, also reabsorb cerebrospinal fluid from the subarachnoid space. The walls of the cerebral veins are very thin while the walls of the dural sinuses are fibrous. Both the veins and sinuses lack valves. The dural sinuses eventually drain into one of the two internal jugular veins. In most individuals one of the internal jugular veins is dominant, usually the right one [3].

Venous angiogram demonstrating the drainage from sagittal sinus into the two transverse sinuses, which became the sigmoid sinuses. The final drainage is into the two internal jugular veins. The jugular bulb is situated at the junction between the internal jugular vein and the sigmoid sinus.

Dural venous sinuses

The major venous sinuses are the superior sagittal sinus, inferior sagittal sinus, sigmoid sinus, transverse sinus, straight sinus and cavernous sinus.
Superior sagittal sinus—this sinus lies in the attached margin of the falx cerebri and receives numerous superficial cerebral veins. Where the falx joins the tentorium cerebelli, the sinus turns laterally to become one of the transverse sinuses, usually the right one.
Inferior sagittal sinus—this lies in the free margin of the falx cerebri and runs posteriorly to join the straight sinus in the midline of the tentorium cerebelli.

Straight sinus—this sinus receives blood from the inferior sagittal sinus and great cerebral vein that drains from deep parts of the brain. The
straight sinus usually turns left to become the left transverse sinus.

Sigmoid sinuses—each sigmoid sinus lies in an S-shaped groove in the petrous part of the temporal bone and in the occipital bone. The groove carries the sinus downward to the posterior part of the jugular foramen, where it becomes the internal jugular vein.

Cavernous sinuses—each cavernous sinus runs on either side of the sphenoid bone between the dura of the middle cranial fossa and the periosteum covering the bone. The two sinuses communicate with each other across the midline near the pituitary where it is joined by the ophthalmic veins and the central retinal veins. The superficial cerebral vein also drains into the roof of the sinus. Through the foramen ovale, the sinuses communicate with the petrous sinuses. The cavernous sinuses also communicate with the facial veins. Various nerves and arteries also traverse through the cavernous sinus.

Basilar venous plexus—this plexus of veins lies on the clivus and provides communication between the internal verterbral venous plexus and the veins and venous sinuses in the cranial cavity.

Normal cerebral blood flow and metabolism

Normal cerebral blood flow (CBF) is approximately 50 mL/100 g/min. This represents the average blood flow for the whole brain; blood flow to the gray matter is higher at 80 mL/100 g/min, whereas flow to the white matter averages 20 mL/100 g/min. The average brain receives about 14% of the cardiac output. Cerebral metabolic rate for oxygen (CMRO2) averages about 3.2 mL/100 g/min, with the gray matter consuming approximately 6 mL/100 g/min and white matter consuming about 2 mL/100 g/min. Consequently, the normal arteriovenous oxygen content difference is about 6.4 vol %, corresponding to a jugular bulb oxygen saturation of between 65–70% in an individual with a normal hemoglobin concentration. Glucose is the main energy substrate used by the brain except during periods of starvation or hyperglycemia where ketones are used as an alternative energy source. At rest, up to 92% of the adenosine triphosphate (ATP) in the brain comes from oxidative metabolism of glucose. Lactate is also consumed in very small quantities by the brain under normal circumstances. However, there is little storage capacity for energy substrate in the brain, as demonstrated by the fall in ATP levels to zero within 7 minutes after termination of the oxygen supply. Therefore, the brain is dependent upon a constant supply of oxygen (aerobic metabolism) and glucose (glycolysis) by the blood (perfusion).

The energy requirements for the brain can be compartmentalized to basal and functional needs. Basal energy is required for maintenance of cell integrity with electrochemical gradients; cellular transport of molecules; synthesis of proteins, lipids, and carbohydrates; and the production, storage, release, and reuptake of transmitters. Functional energy is expended in neuronal functioning including generation of electrical activity by the pyramidal cells. About 40% of the energy is used for basal needs, whereas functional activity consumes about 60%.

Measurement of cerebral blood flow

Numerous techniques are now available for monitoring of CBF, although most are expensive, time-consuming, and seldom practical for routine clinical uses. These methods can measure global, regional, or local CBF.

Global CBF
The Kety-Schmidt technique of nitrous oxide washing is considered to be the gold standard for measurement of hemispheric blood flow [4]. Modifications and adaptations of this technique include argon washing and 133xenon clearance. Recently, a double indicator method to measure hemispheric CBF was introduced [5].

Regional CBF
Regional CBF can be determined using multiple detectors with 133xenon clearance. Regional CBF can also be mapped with xenon CT. Single photon emission CT provides relative qualitative information but not absolute CBF, whereas positron emission tomography will measure absolute regional CBF.
Transcranial Doppler sonography
Transcranial Doppler (TCD) sonography measures CBF velocity in the basal cerebral arteries. Although TCD is not a direct measure of CBF, changes in flow velocity generally correlate well with changes in CBF, except under specific circumstances such as vasospasm. Because it is noninvasive, it allows repetitive, bedside measurement of relative changes in regional CBF. It is particularly suited for the repetitive assessment of cerebral autoregulation [6].

Local CBF
The Laser Doppler measures local CBF in a tissue volume of 1 mm3.
Experimental methods include hydrogen clearance, radioactive or fluorescent microspheres, and autoradiographic measurements, which are only applicable in animal models.

Control of the cerebral circulation

The cerebral circulation is tightly regulated with a number of homeostatic mechanisms. The major influence of the cerebral circulation are (1) metabolism, (2) partial pressure of carbon dioxide (PaCO2), (3) partial pressure of oxygen (PaO2,) (4) viscosity, and (5) blood pressure/cerebral perfusion pressure.

Flow–metabolism coupling

In the absence of pathology, CBF flow is tightly coupled to cerebral metabolism. This occurs both at a global and regional level. During periods of central nervous system activation, CBF increases to accommodate the rapid increase in CMRO2 necessitated by the increased energy requirements for synaptic transmission. Thus, activation of the occipital cortex with light stimulation of the retina is immediately followed with an increase in flow in the posterior cerebral arteries. Epileptic seizures are accompanied by an almost instant increase in global CBF. Flow–metabolism coupling is perhaps the most important control of the cerebral circulation. It is a robust mechanism that is preserved during sleep [7–9] as well as during general anesthesia [10]. It can be observed during the different stages of sleep where light or deep sleep is associated with a 10% decline in CBF, and rapid-eye-movement (REM) sleep has CBF similar to the awake state [7]. Flow–metabolism coupling can also be observed during deep inhalation anesthesia, where regional changes in metabolism are coupled with regional changes in flow [11]. Recent studies have demonstrated that the increase in CBF may transiently exceed the increase in CMRO2 (luxury perfusion), and that the regulation of CBF during neuronal activity is independent of local tissue levels of oxygen [12].

Mediators of flow–metabolism coupling

Adenosine and nitric oxide are two purported mediators of flow–metabolism coupling. Adenosine causes increased cyclic AMP production that results in cerebrovasodilation. Nitric oxide (NO) is an intercellular messenger in the peripheral circulation and in the central nervous system, and causes vascular smooth muscle relaxation and inhibition of platelet aggregation. Antagonists of both adenosine and NO will attenuate the rise in CBF associated with neuronal activation, although neither mediator antagonist alone, nor in combination, will completely abolish the CBF increase in response to neuronal activation [13]. Therefore, other mediators such as H+ ions, adenine nucleotides, potassium, prostaglandins, and vasoactive intestinal peptide, may also be involved in flow–metabolism coupling.

Both sympathetic and parasympathetic neurons may contribute to the neurogenic regulation of flow–metabolism coupling. In rats, stimulation of the sympathetic system causes both increased CBF and CMRO2, while stimulation of the parasympathetic system causes an increase in CBF only. Activation of the central sympathetic system causes a much greater increase in CBF and CMRO2 than activation of the extrinsic sympathetic system that originates extracranially. The role of the sympathetic system in regulation of CBF in humans remains unknown, although it is thought that sympathetic stimulation shifts the autoregulatory curve to the right.

Temperature effects on flow–metabolism coupling

Hypothermia causes a reduction in CMRO2, thereby decreasing CBF via flow–metabolism coupling. CBF decreases approximately 5% to 7% per degree Centigrade. Reduction of the brain temperature to 15°C will reduce CMRO2 to 10% of normothermic values. Hypothermia causes a reduction in both the basal metabolism required for maintenance of cellular integrity and the functional metabolism of the CNS. Anesthetic agents affect only the functional component of the CMRO2.

CO2 vasoreactivity

The cerebral circulation is exquisitely sensitive to changes in PaCO2. In normal subjects CBF increases linearly by 2% to 4% per mmHg PaCO2 within the range of 25 to 75 mmHg. This makes PaCO2 the most potent physiologic cerebral vasodilator. The change in CBF occurs within seconds after PaCO2 is changed, and complete equilibration occurs within 2 minutes [14]. The brisk response of the cerebral vasculature to carbon dioxide (CO2) is caused by the rapid diffusion of arterial CO2 across the blood–brain barrier (BBB) and into the perivascular fluid and cerebral vascular smooth muscle cell. CO2 causes a reduction in the perivascular pH, which leads to cerebral vasodilation and increased CBF. Both CO2 and bicarbonate ions exert their effects on the cerebrovasculature via changes in the extracellular fluid pH, and not by direct action [15]. Although CO2 is a potent cerebral vasodilator, arterial H+ ions do not affect the cerebrovasculature because they do not readily diffuse across the intact BBB, and therefore, cannot lower the perivascular pH of the cerebral vessels. Consequently, metabolic acidosis and alkalosis do not affect cerebral vascular tone, as do respiratory acidosis and alkalosis [16].

The changes in CBF associated with alterations of arterial CO2 are not maintained for prolonged periods. During chronic hypercapnia maintained for 6 hours in dogs, Warner et al. [17] demonstrated an adaptive increase in the cerebrospinal fluid (CSF) pH that was associated with a decrease in CBF. The pH change was accompanied by an increase in the CSF bicarbonate ion. Similarly, during chronic hypocapnia, the CSF pH gradually decreases toward baseline as CSF bicarbonate concentration decreases and CBF increases [18].

Mechanism of CO2 vasoreactivity

The mechanism for CO2 vasoreactivity appears to be regulated by local mediators, rather than by chemoreceptors in the periphery because their denervation does not alter the CBF response to changes in arterial CO2. The molecular pathway by which perivascular pH influences cerebral vascular tone has not been clearly defined. From mice to humans, it has been demonstrated that NO is partially responsible for CO2-mediated cerebral vasodilation. Schmetterer et al. [19] demonstrated a significant reduction in mean flow velocity of the middle cerebral artery to hypercapnia in healthy human volunteers after administration of an NO synthase (NOS) inhibitor. However, NOS inhibitors do not completely ablate CO2 vasoreactivity, and NO may be more important in regional rather than global regulation of vasoreactivity. The cerebral cortex in primates was the only site in which NOS inhibitor attenuated the CBF response to increasing arterial CO2 concentration [20]. Site-specific responses indicate either the existence of more than one pathway of CO2-mediated vasodilation, or that different regulatory mechanisms occur at different locations. Moreover, CO2 vasoreactivity in neuronal NOS knockout mice was found to be the same as in wild-type mice [21]. Other putative mediators of CO2 vasoreactivity include prostaglandin E2 (PGE2) and cyclic guanosine monophosphate. Indomethacin, an inhibitor of prostaglandin production, causes potent attenuation of CO2 vasoreactivity, which is restored upon addition of PGE2[22].

Conditions that alter CO2 vasoreactivity

Global CO2 vasoreactivity is relatively robust, and is only abolished in brain-damaged patients in terminal conditions. However, there are many conditions in which it may be attenuated. Patients with severe carotid stenosis, head injury, subarachnoid hemorrhage (SAH), cardiac failure, or severe hypotension, in which the compensatory cerebral vascular response is already exhausted, may have a decreased response to changes in CO2 compared to healthy subjects. Local loss or decrease in response to CO2 in carotid stenosis has been demonstrated, and can be used to predict the need for intraoperative shunting, and to predict which patients with asymptomatic disease might benefit from surgery [23]. Similarly, impaired CO2 vasoreactivity can be used to prognosticate in severe head-injury patients [24]. Patients with aneurysmal SAH frequently demonstrate a reduced response to hypocapnia, and may have absent response to hypercapnia when vasospasm is present [25,26]. Cardiac failure patients demonstrated reduced CO2 vasoreactivity that was associated with reduced left ventricular ejection fraction [27]. Hypercapnia, under these pathologic conditions, may induce cerebral ischemia by causing vasodilation of unaffected regions of the brain and vessels, and diverting blood flow away from the maximally dilated, diseased regions. This phenomenon is known as cerebrovascular “steal.” Severe hypotension would also maximally vasodilate the cerebral vasculature, and results in a temporary loss of CO2 vasoreactivity [28]. The extent of attenuation of CO2 vasoreactivity is probably influenced by the choice of hypotensive agent, because different hypotensive agents demonstrate different reductions in CO2 vasoreactivity [29]. Hypothermia does not seem to affect CO2 vasoreactivity [30,31], but advancing age (>fourth decade) in the female gender is associated with a decline in CO2 responsiveness unless subjects are on hormone replacement therapy [32].

Hypoxemia-induced cerebral vasodilation

Compared to PaCO2, the influence of PaO2 on the cerebral circulation is mild and of much less clinical significance. CBF generally does not increase appreciably until PaO2 decreases below 60 mmHg, although one study reported a 23% increase in CBF in humans when PaO2 was decreased from 100 to 65 mmHg [33]. The response to hypoxemia is not as brisk as the response to changes in PaCO2, because equilibration of CBF takes approximately 6 minutes after the establishment of hypoxemia. On the other hand, the effect of hyperoxemia is less certain, as studies have shown either a slight decrease in CBF velocity or no change at all [19,33]. Traystman et al. [34] demonstrated that the mechanism of hypoxemia-induced vasoreactivity is not dependent upon baroreceptors or chemoreceptors in dogs. Hypoxemia may induce cerebral vasodilation via anaerobic glycolysis and lactic acid production causing decreased extracellular pH and subsequent vasodilation. However, Koehler et al. [35] demonstrated that pH changes during hypoxemia are only partially responsible for the increased CBF. Many studies have demonstrated that release of adenosine is necessary for the vasodilatory response to hypoxemia [36,37]. In animal models, adenosine activates large conductance calcium-activated potassium channels and ATP-sensitive potassium channels that contribute to vasodilation [38]. NO has also been implicated as a mediator, because NOS inhibitors will reduce the increase in CBF, which occurs during hypoxemia [39,40].

Effects of viscosity on CBF

Viscosity of blood is primarily a function of the hematocrit. Decrease in viscosity is usually secondary to hemodilution, and CBF increases as a result of the improved rheology of the blood flow in the cerebral vessels, as well as a compensatory response to decreased oxygen delivery [41].
Blood pressure or cerebral perfusion pressure (cerebral autoregulation)

Normal flow, pressure, and resistance relationships

The relationship between flow and pressure can be simplistically described by the equation where F = flow, P = pressure, and R = resistance. However, the cerebral vascular bed is not rigid. Resistance to flow is dependent on the length of the blood vessel, the viscosity of the fluid going through it, and the caliber of the vessels. Thus, laminar flow through a cerebral vascular bed can be described by the Poiseuille's equation: where F = flow, r = vessel radius, ΔP = pressure gradient, η = viscosity, and L = length. Thus, RESISTANCE = (8 ηL)/(πr) [4].

However, the brain and its blood vessels are encased in the rigid cranium and, therefore, subjected to the surrounding pressure (intracranial pressure—ICP). The net cerebral perfusion pressure (CPP) is generally defined as the difference between mean arterial blood pressure (MAP) and ICP. It should be noted that the cerebral venous pressure at the junction between the cerebral veins and the dural sinuses is usually slightly greater than ICP (necessary to allow venous flow). When ICP is low but jugular venous pressure (JVP) is high, (e.g., when there is venous obstruction at the neck), then CPP = MAP − JVP.

Under normal physiologic conditions, changes in MAP between 60 and 160 mmHg in the average individual produces little or no change in CBF [42]. This homeostatic mechanism of cerebral autoregulation with in vivo vasoconstriction and vasodilation in response to changes in blood pressure was first observed by Fog [43]. Cerebral autoregulation ensures that as MAP increases there is increased resistance from a reduction in the caliber of the small cerebral arteries and arterioles. This protects the cerebral arterioles and the brain from elevation in MAP. This adaptive mechanism also maintains adequate CBF when MAP or CPP decreases. Thus, cerebral arterioles dilate as MAP decreases, and constrict as MAP increases. Beyond these limits of autoregulation, CBF is directly proportional to MAP and can be described as pressure-dependent or pressure-passive. There are some areas of the brain that are more at risk for ischemia than others. The watershed areas between the anterior, middle, and posterior cerebral arteries, as well as the areas between the superior and inferior cerebellar arteries are particularly susceptible to ischemia as MAP decreases. These regions have resting MAP that is lower compared to more proximal territories supplied by the major arteries and are, therefore, the first ones to reach a critical threshold when systemic MAP decreases. When MAP exceeds 150–160 mmHg, CBF begins to increase, and vessels may begin to leak with extravasation of blood into the extravascular space. The MAP at which CBF increases is termed “breakthrough” or the upper limit of cerebral autoregulation [44]. Sudden decrease in CBF occurs at the other inflection point, or the lower limit of autoregulation.

Mechanisms of autoregulation

The precise physiologic process accounting for cerebral autoregulation is unknown, and may represent a combination of metabolic, myogenic, and neurogenic mechanisms.

The metabolic mechanism

This stipulates that autoregulation is mediated by the release of vasodilator substance that regulates the cerebrovascular resistance to maintain CBF constant. Although no specific substance fits all experimental observations, adenosine, a potent cerebral vasodilator, formed from breakdown of ATP when neuronal demand of oxygen exceeds supply is a prime candidate [45]. Adenosine can be found in increased concentration in cerebral tissue as systemic blood pressure falls towards the lower limit of autoregulation. In fact, brain adenosine concentration doubles within 5 seconds of decreasing blood pressure [46]. Cortical activation via contralateral peripheral stimulation is also immediately followed by adenosine release and regional vasodilation [47]. It has been suggested that NO exerts an influence on basal and stimuli-mediated cerebrovascular tone. The mechanism of NO-induced cerebral vasodilation probably involves cyclic guanosine monophosphate and a decrease in intracellular calcium. It is unclear to what extent NO affects cerebral autoregulation in both healthy patients and in patients with traumatic brain injury. Although earlier studies suggest that NO has no influence on cerebral autoregulation, Jones et al. [48] recently described an increase in the lower limit of autoregulation with NOS inhibitors. Other transmitters/substances that have been proposed as mediators of autoregulation include protein kinase C [48], melatonin [49], prostacyclin, activated potassium channels, and intracellular second messengers [50].

The myogenic mechanism

This theory of pressure-dependent myogenic tone, first proposed by Bayliss in 1902, was not experimentally verified until approximately 50 years later. The myogenic theory states that the basal tone of the vascular smooth muscle is affected by change in perfusion or transmural pressure, and the muscle contracts with increased MAP and relaxes with decreased MAP. Studies suggest that there may be two myogenic mechanisms involved in cerebral autoregulation: a rapid fast reaction to pressure pulsations, and a slower reaction to change in MAP. This adaptive process appears to be initiated within the first 400 milliseconds (rapid and rate-dependent response), and is probably completed in a few minutes by the slower and rate independent component of the autoregulatory process. The slower secondary component appears to be the dominant force in regulating CBF. Autoregulation might also be invoked by incremental and nonpalatial pressure. However, constant pressure elevation is probably not a sufficient stimulus to maintain sustained vascular contraction. Some investigators believe the myogenic mechanism sets the limits of autoregulation, whereas the metabolic mediators are responsible for cerebral autoregulation itself.

The neurogenic mechanism

Perivascular innervation of the cerebral resistance vessels and the specific neurotransmitter contained within the perivascular nerve fibers may also modulate vascular response to changes in blood pressure. However, the specific mechanisms by which the central nervous system exerts control on the cerebral vasculature are poorly understood. Although acetylcholine is the most abundant perivascular neurotransmitter, the list of neurotransmitters involved in this neural response includes norepinephrine, neuropeptide Y, cholecystokinin, acetylcholine, vasoactive intestinal peptide, and calcitonin gene-related peptide [51]. Experimentally sympathetic stimulation can shift the autoregulatory curve to the right, thus protecting the brain against severe elevation of MAP.

Abnormal autoregulation

Autoregulation can become impaired or abolished by a variety of causes including trauma, hypoxemia, hypercapnia, and high-dose volatile anesthetics. Physiologically, hypercapnia (PaCO2>60 mmHg) will consistently impair cerebral autoregulation [52]. Clinically, the neurologic disorders where autoregulatory impairment may contribute to the pathophysiology include ischemic cerebrovascular disease, subarachnoid hemorrhage, and traumatic brain injury (TBI). Abnormal autoregulation can range from minimal impairment to complete loss and can be classified as “intact,” “impaired,” or “abolished.” However, autoregulation is not an all-or-none phenomenon, but rather represents a continuous spectrum of adaptive response in cerebrovascular resistance to a change in perfusion pressure. In patients with absent autoregulation, systemic hypertension may lead to cerebral hemorrhage and edema formation, whereas a decrease in blood pressure may turns areas with ischemia into areas of infarction. In patients with subarachnoid hemorrhage with impaired autoregulation, induced hypertension may ameliorate ischemic deficits and improve outcome; thus, the risk of increased cerebral edema and hemorrhage must be balanced against the benefits of improved perfusion. Patients with TBI frequently suffer from cerebral ischemia and loss of autoregulation, and a relatively high-maintenance MAP may be indicated. Because the compensatory vasoconstriction mediated by the autoregulatory response would result in a decrease in ICP, elevation of MAP may be beneficial even in patients with preserved cerebral autoregulation. Moreover, some TBI patients may have a rightward shift of the lower limit of autoregulation, necessitating the maintenance of a higher MAP than normal (see below). Documentation of the cerebral autoregulatory capacity would often facilitate clinical management of these patients.

Limits of autoregulation

Although the limits of cerebral autoregulation are often stated as 60 and 160 mmHg, there is considerable variation in the limits among normal individuals. Pathologically, these limits can be affected by a number of conditions. The classic examples are chronic hypertension and traumatic brain injury. In chronically hypertensive adults, the autoregulatory curve is shifted to the right, and a MAP >160 mmHg may not cause any increase in CBF. In patients with traumatic brain injury, cerebral autoregulation may be impaired or abolished, or similarly shifted to the right [53,54].

Autoregulation testing

Determination of autoregulation requires monitoring of CBF (see above) with simultaneous change in MAP effected either spontaneously or provocatively, and in the latter category, either pharmacologically or nonpharmacologically. The gold standard is static testing, with measurement of CBF at two different levels of steady-state MAP. With the advent of TCD monitoring, it is now possible to test static autoregulation repetitively in the bedside. Because of the high temporal resolution of TCD, it is also possible to test dynamic as well as static cerebral autoregulation. Dynamic autoregulation is performed by monitoring the change in CBF velocity in response to a transient decrease in MAP from sudden deflation of bilateral thigh cuffs that have been inflated for a duration of 3 minutes [55]. The autoregulatory index (ARI) is derived from a mathematical model, and reflects how quickly middle cerebral artery flow velocity (Vmca) returns to baseline while the MAP remains low (Appendix 1). An abnormal ARI reflects either a decreased capacity of the autoregulatory response or an increased latency in the response. An ARI derived from static autoregulation measurements quantifies the change in cerebrovascular resistance (CVR) in response to change in MAP during steady state without regard to latency (Appendix 2)[6]. The autoregulatory stimulus during static testing often necessitates pharmacologic manipulation of blood pressure. On the other hand, dynamic testing offers the advantage of quantifying the speed of the response without use of any pharmacologic agents and tests the response to hypotension instead of hypertension. Despite the fact that each testing method may assess different aspects of the cerebral autoregulatory response, good correlation between them have been demonstration under conditions of both intact and impaired autoregulation [56].

Recently, the transient hyperemic response (monitored by TCD) from unilateral carotid compression has been proposed as a test of cerebral autoregulation [57]. However, the uncontrolled nature of the provocative stimulus makes this unreliable, and is at best a semiquantitative test.

Conclusion

Remarkable progress has been made in the understanding of the control of the cerebral circulation in health and disease states during the last 20 years. This is in part due to the multidisciplinary basic science research and clinical research into the mechanisms of regulation of CBF. In this article we have attempted to describe aspects of CBF physiology relevant to the practicing anesthesiologist. Anesthesiologists, in their daily practice, knowingly and unknowingly manipulate and modulate the cerebral circulation. A thorough understanding should improve patient care and outcome in those with neurologic disease.

Appendix 1

Dynamic cerebral autoregulation was calculated by the computer using the following algorithm. The Autoregulation Index (ARI) is scaled 0–9. DP = (MAP−cMAP)/cMAP−CCP)• x2 = x2 + (x1−2D•x2)/f•T) x1 = x1+(dP−x2)/(f•T) mV = cVmca•(1+dP−k•x2) dP = change in MAP due to cuff release cMAP = baseline MAP value before cuff release CCP = critical closing pressure (calculated by the computer) x1 and x2 = variables that were assumed to be zero during the control periodD = damping factorf = sampling rateT = time constant mV = mean velocity cVmca = mean middle flow velocity before cuff deflationK = autoregulatory dynamic gain

Appendix 2

The ARI scaled 0–1 using the static method of testing is calculated as follows: ARI = % ΔeCVR/% ΔMAP And e CVR = MAP/VmcaARI = Autoregulation Indexe CVR = estimated cerebrovascular resistance MAP = mean arterial pressure Vmca = middle cerebral artery flow velocity

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