EVALUATION WITH INVASIVE AND NONINVASIVE TECHNIQUES

ANESTHESIA FOR THE PATIENT WITH NEUROLOGIC DISEASE

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EVALUATION WITH INVASIVE AND NONINVASIVE TECHNIQUES David A. Stump, PhD, and David M. Colonna, MD

As with nearly all physiologic monitoring modalities available to anesthesiologists and critical care physicians, there is little evidence that interventions triggered by information acquired from patient monitors actually improve clinical outcomes. Nevertheless, there are convincing data demonstrating that critically diminished cortical blood flow decreases brain function and viability. For example, Sharbrough et a142 demonstrated at the Mayo Clinic that decreases in cortical blood flow to levels less than 20 mL X 100 8-l X minute abolish spontaneous, electroencephalogram activity. Cortical blood flow to levels 15 mL X 100 8-l X minute or less abolish somatosensory evoked potential^,"^ and this level of oligemia, if maintained, can produce permanent brain injury.36Therefore, it is rational (though unproven) to base therapeutic interventions upon measurements of cerebral blood flow (CBF), as well as other parameters which affect CBF (blood pressure, C02, intracranial pressure). This article is divided into three parts. The first describes basic theories upon which CBF measurement, methodologies are based; the second explains different CBF measurement techniques; third, the application of different CBF measurement techniques for both research and clinical applications are discussed. Understanding CBF measurement techniques, both their application and individual shortcomings, is important because patients are subjected

From the Departments of Anesthesiology and Neurology, The Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, North Carolina

ANESTHESIOLOGY CLINICS OF NORTH AMERICA

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VOLUME 15 NUMBER 3 SEPTEMBER 1997

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daily to anesthesia, cardiopulmonary bypass, carotid endarterectomy with temporary occlusion of common carotid artery blood flow, or craniotomy with brain retraction, all of which may profoundly affect CBF. Anesthetics, such as barbiturates and volatile anesthetics, alter brain metabolism and blood flow, thus affecting brain well-being. And, finally, patients endure various physiologic perturbations (e.g., hypoxemia, hypercarbia, hypocapnia, hypotension, hypertension, seizures), which significantly affect cerebral blood flow. Thus, an understanding of the advantages, limitations, and applications of various methodologies used to measure CBF would, in the authors’ opinions, prove useful in the care of patients at risk for brain injury. Though the technical limits and reliability of cerebral blood flow methodologies play an important role in the interpretation of CBF data, only the essential elements of each methodology are discussed here. In addition, some CBF flow measurement techniques, because of their nature, are used in nonhuman research only (injection of radiolabeled microspheres, venous outflow methods), and will be examined more briefly in this article than those used in clinical research. Nevertheless, as C.S. Roy and C.S. Sherrington, two pioneers of cerebral blood flow measurement, state: We must on this account say more about the technology of our subject than would be necessary were the subject a simpler one.4O

CHARACTERISTICS OF THE IDEAL CBF MEASUREMENT SYSTEM What characterizes the ideal CBF methodology? The ideal methodology should have:

A high degree of resolution, accuracy, and reliability (CBF in specific anatomic brain structures should be precisely resolved and accurately measured) Rapid CBF resolution capable of providing real-time measurements Minimal patient risk (e.g., noninvasive, no ionizing radiation) Low-cost use, interpretation, and storage Freedom from motion, radio frequency, or electrical artifact Easy portability Alarms alerting caregivers of significant alterations in CBF Sturdy construction with minimal service requirements Flexible electrical power requirements with internal, rechargeable backup batteries Capability for reprogramming for software upgrades, as well as for exporting data to hospital record-keeping systems An ergonomically sound interface and quiet during operation. The authors readily admit that no such device exists that meets the previously mentioned criteria

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Basic Concepts There are three concepts needed to understand the methodologies currently used to estimate CBF. Because CBF is a quantitative measurement, the basic formulae used in its estimation will also be presented. The Fick Principle

This principle, derived from Fick's law, was described by the German physiologist, Adolph Fick (1829-1901). Whereas Fick's Law states that the mass of solute diffusing through a medium per unit of time is proportional to the concentration gradient,7 Fick's principle states that the quantity of a substance taken up by an organ (Qt) is equal to the product of the flow through the organ (F,) and the arteriovenous concentration difference of the substance (Ca - Cv)." Thus, Qt

=

F, X (Ca-Cv)

(1)

And when the quantity varies with time:

F,

=

Qt

(Ca - Cv) x dt

This formula is used in other areas of medical practice as well (e.g., total body O2 consumption = cardiac output X [paO, - pvO,], where pa02 is arterial p02, and pv0, is mixed venous PO,). Kety-Schmidt Modification of the Fick Principle

Kety and Schmidt desired to measure cerebral blood flow in humans. They recognized that the major obstacle in measuring CBF in humans using the Fick principle lay in quantitating the diffusible tracer within the entire brain. They deduced that if the concentration of the tracer in the brain at one point in time was known (C,), then blood flow (F,) per unit of mass could be derived for that organ. Thus, tissue perfusion rather than total organ blood flow is derived from these measurements:

F,

=

ct (Ca - Cv) x dt

(3)

In addition, they observed that the concentration of the tracer in the organ (C,) approximates the concentration of the tracer in venous blood draining that organ; thus, they were able to calculate brain tracer concentration by measuring arterial and jugular venous concentrations.Is

F,

=

cv (Ca - Cv) x dt

(4)

While allowing patients to breathe to equilibrium 15% nitrous oxide as the diffusible tracer, Kety and Schmidt measured arterial and jugular

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venous concentrations of N 2 0 over multiple time points. They then constructed curves representing uptake ("wash in" curves [Fig. 11) of N20, from which ipsilateral hemispheric CBF could be calculated.2x Doppler Effect

The effect was described by Christian Doppler (1803-1853), an Austrian physicist, in his 1842 manuscript Uber das farbige Licht der Doppelsterne ("Concerning the Colored Light of Double Stars"). He observed that sound- or light-wave frequencies are altered by the relative motion of the sound or light source or the detector.46Therefore, if a sound wave of known frequency is transmitted into the brain, striking blood cells traveling toward the detector, then there will be a "violet shift, " an increase in the frequency of the reflected wave, as opposed to a "red shift, " a decrease in the reflected wave's frequency, if the blood cells were traveling away from the detector (Fig. 2). This Doppler shift can be quantitated, and hence, blood flow velocity ~ a l c u l a t e d . ~ ~ Methods Measurement of Cerebral Vascular Diameter

After surgical exposure of pial arterioles on the brain surface, their diameter may be measured in real time using video microscopy. Though this method does not quantitate or even estimate cerebral blood flow, this technique has been extremely useful for examining the mechanisms that regulate cerebral vascular tone during autoregulation, hypoxia, and

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Minutes of Inhalation Figure 1. Arterial (A) and venous (V) concentrations of nitrous oxide during inhalation of 15% nitrous oxide by human subjects. Samples were taken from a jugular bulb catheter (V) and from a peripheral artery catheter (A). (Redrawn from Kety SS, Schmidt CF: The determination of cerebral blood flow in man by use of nitrous oxide in low concentrations. Am J Physiol 143:53, 1945; with permission.)

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Figure 2. A Doppler transducer (RX) insonates a blood vessel containing a red cell with a red blood cell moving towards the transducer at a velocity (V). The transducer’s energy wave is sent towards the red cell, moving through the brpin at velocity (C) and wavelength (A,). Because the red cell is moving towards the transmit,ed wave, the reflected wave (like an echo) returns to the transducer at velocity (C), but with a new, higher frequency (A2).47 Using the parlance used to describe light waves, the reflected wave is “violet shifted.” The amount of violet shift is related to the blood flow velocity. (Reproduced from Transcranial Doppler. Newell DW, Aaslid R, eds. New York, Raven Press, 1992; with permission.)

hypercarbia, and after ischemia. By infusion of various substances (e.g., vasoactive peptides, such as substance P, and calcitonin gene-related peptide)” upon the brain surface, their roles in regulating cerebral vascular tone have been elucidated. Because of the invasive nature of this method, this technique is used in animal preparations only. Use of Electromagnetic Flow Probes

Placement of an electromagnetic flow probe around a blood vessel allows continuous measurement of flow through that vessel.8 This technique is based on the Faraday Law of electromagnetic induction, whereby an electromagnet is placed around a vessel, producing a magnetic field perpendicular to the axis of blood flow. Blood acts as a moving conductor through the magnetic field, inducing an electrical charge proportional to the flow through the vessel8 The diameter of the probe must closely approximate that of the vessel examined for maximal flow accuracy. To measure flow to the entire brain, all of the feeding vessels (carotid and vertebral arteries) must be isolated and affixed with probes. In an effort to decrease surgical preparation time in an experimental animal, the vertebral arteries are often ligated and probes placed around each internal carotid artery. An additional limitation in some animal models is the absence of a true internal carotid artery

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because of the presence of a carotid rete mirabile (e.g., goatI4 and pig33). This methodology is not applicable in humans. Laser Doppler Flowmetry Laser Doppler flowmetry (LDF) exhibits a number of excellent properties; the device is small, lightweight, inexpensive, and provides continuous flow measurement to a discrete area of brain. Coherent light from a laser source (usually helium-neon) is carried to the probe via a fiberoptic cable. The probe is placed on the brain area of interest, and laser waves penetrate the tissue. When the light strikes moving red blood cells in brain parenchyma, a Doppler shift is produced and light is reflected back to the probe. The reflected light is quantitated by a photo detector and the Doppler-shifted signal analyzed by a microprocessor.', 5, The final output is a graphical representation of pulsatile blood flow. This technique does have several limitations. For example, there are difficulties calibrating the device in a specific patient and different software and hardware difficulties associated with acquiring, analyzing, and outputting LDF data. For those reasons, measured flow is expressed in arbitrary LDF units.z,5, 47 Assuming stable physiologic conditions, LDF measurements are stable, and changes in CBF are therefore expressed as percentage change from a baseline value.21,22 Because CBF can be measured continuously, this device has been used intraoperatively to determine CBF to areas at risk from brain retractor injury4and as a monitor to determine adequacy of brain tissue perfusion in patients at risk for vasospasm after subarachnoid hemorrhage. LDF is used to determine the effectiveness of hemodilution, hypertension, and hypervolemia therapy in these This device has several disadvantages. First, it is invasive. Although the probes used often have a tip diameter less than 2 mm, there is risk of introducing infection. Second, the volume of tissue analyzed is very small, often less than 3 mm3.36Therefore, any conclusions made about total brain perfusion must be drawn from LDF data gathered from only a small percentage of total brain parenchyma. Third, blood clots forming between the probe tip and the brain may obscure laser light transmission or reflection. Further, this technique is subject to motion artifact produced by either probe or patient movement. Because of these limitations, LDF must be analyzed in conjunction with patients' neurologic examinations, blood pressure, intracranial pressure, central venous pressure (CVP), pC0, and physiologic parameters. LDF has also been used in animal experiments related to the brain and its regulation of blood flow in a variety of circumstances.'6,48 A recent report demonstrated that marked increases (-130% above normal) in cortical CBF in an animal model produced LDF overestimations when compared to direct cortical CBF measured via the 14C-iodoanti-

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pyrine method.17Despite these limitations, LDF, by its ability to continuously measure CBF, is a very powerful research tool, especially when studying rapid changes in CBF (e.g., autoregulation latencies).ls Venous Outflow

This method is simple in concept, but technically difficult to execute. This method is based on the premise that continuous measurement of the entire venous outflow of the brain over a given time is equal to cerebral blood flow. The degree of surgical trauma needed to divert all of the cerebral venous blood flow is considerable. Some researchers have cannulated the sagittal sinus and occluded the transverse sinuses to then measure sagittal sinus flow. This procedure has been used in animal preparations, but has fallen in popularity when compared to less invasive techniques. Thermal Diffusion

This method of CBF estimation is derived from the original observation, published in 1952, that changes in tissue thermal conductivity were proportional to changes in tissue blood flow. Evolution of thermal probe design allowed researchers to measure cortical CBF that correlated favorably with 133Xeclearance method^.^ For the thermal diffusion probe to function properly, it must be placed on an area of cortex free of major surface blood vessels and sulci. Because of the probe size, only a small area of cortex has blood flow analyzed. Thus, this device shares the same shortcoming of LDF, namely, that one must infer the adequacy of cortical blood flow in the brain as a whole by analyzing blood flow data gathered from a small strip of cortex. This may not be a valid assumption. Also, thermal diffusion blood flow measurement is invasive, requiring the placement of a probe on the brain surface. Transcranial Doppler Sonography

Transcranial Doppler sonography (TCD) uses sound waves directed toward a target blood vessel (insonation) and the measurement of the Doppler shift of the reflected wave. From this, flow velocity is calculated. The TCD probe is usually applied over one of four areas ("windows") upon the temporal bone to insonate the middle cerebral artery (MCA) (Fig. 3). Because the sound waves are transmitted through temporal bone, increased bone thickness can adversely affect insonation of the MCA. As previously alluded to, changes in MCA diameter can change flow velocity, assuming flow is constant, such that Q

=

Vm2

(5)

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Figure 3. Temporal sites for transcranial Doppler probe insonation of the middle cerebral artery: the frontal (F), anterior (A), middle (M),and posterior (P) windows are depicted. (Reproduced from Transcranial Doppler. Newell DW, Aaslid R, eds. New York, Raven Press, 1992; with permission.)

where Q is the rate of blood flow, v is flow velocity, and r is the radius of the blood vessel.2oThus, v = -Q mz This method of estimating cerebral blood flow meets several important criteria that describe an ideal CBF monitor: continuous, noninvasive, inexpensive, nonionizing radiation and the standard data output is intuitively easy to interpret. There are, however, two potential problems. First, the TCD measures blood flow velocity and not flow. Second, to interpret TCD-acquired flow velocity data, one must be mindful that changes in vessel diameter (the middle cerebral artery is the most commonly insonated vessel) will change flow velocity, even when flow stays the same. This is very important for a simple reason. If one is measuring continuous TCD flow velocity as a representation of CBF, one is assuming that middle cerebral artery (MCA) diameter is constant. Fortunately, for users of TCD, basal cerebral conduction vessels at the Circle of Willis [MCA, anterior cerebral artery (ACA), and so on] do not appreciably change their diameter with changes in blood pressure, PCO~,’~ or with volatile or intravenous anesthetic^.^^, 41 Although correlation between absolute TCD flow velocities and CBF are not strong, changes in flow velocity have correlated well with changes in CBF measured by more traditional means.29In summary, for patients who are anesthetized and have TCD blood flow velocities measured, relative changes in TCD velocity will mimic relative changes in CBF.

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Cerebral blood flow velocity is characterized by unidirectional blood flow. Thus, even during ventricular diastole, cerebral arterial blood continues to move forward, perfusing the brain during the entire cardiac cycle. This is easily visualized by TCD (Fig. 4); however, during pathologic conditions where the intracranial pressure (ICP) matches diastolic

t

Normal Condition

SAP systolic diastolic

Flow Velocity

~cp Normal flow

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SAP

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L- AAA Flow Velocity

High resistance flow

Flow Velocity

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Oscillating flow

lcPm

Flow Velocity

Zero flow

Figure 4. This figure shows the relationship of systolic (syst.) and diastolic (diast.) systemic arterial blood pressure (SAP) with intracranial pressure (ICP) and blood flow velocity measured by TCD. At the top is the normal condition, with foiward arterial flow throughout the cardiac cycle. However, when ICP equals diastolic BP, there is blood flow only during ventricular systole, and when ICP exceeds diastolic BP, there is reversal of blood flow during diastole. This reversal of blood flow is what is known as an oscillating blood flow pattern (the third TCD pattern from the top). (Reproduced from Hassler W, Steinmetz H, Gawlowski J: Transcranial Doppler ultrasonography in raised intracranial pressure and in intracranial circulatory arrest. J Neurosurg 68:745,1988; with permission.)

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blood pressure, arterial blood flow ceases in the brain during diastole. If ICP increases further, exceeding diastolic blood pressure, this produces diastolic back flow, producing what is known as an oscillating TCD pattern. This finding is highly suggestive of a grave patient prognosis. Indeed, in a series of 71 patients with intracranial hypertension and oscillating TCD patterns, none survived (Fig. 5)." TCD sonography yields other important information about the cerebral circulation other than blood flow velocity, namely, the presence of microemboli. The ability to detect emboli has yielded fascinating insights into perioperative brain injury after cardiopulmonary bypass. Using continuous wave Doppler sonography of the common carotid artery in patients undergoing cardiopulmonary bypass, the Bowman Gray School of Medicine group demonstrated that severity of neuropsychiatric deficits post-bypass is positively associated to the number of emboli detected intraoperative1y.J' Physicians from the Netherlands performed TCD during carotid endarterectomy and revealed that severity of embolization during carotid dissection (before cross-clamping of the common carotid artery had occurred) predicted the presence of new brain defects on postoperative MR images.27Thus, cerebral microembolization represents an important mechanism of perioperative brain injury during certain surgeries. TCD may aid researchers in understanding the pathophysiology of these insults; however, new users of TCD technology are advised that few validation studies exist that correlate TCD signals with known emboli. Thus, discretion must be used when searching perioperative TCD scans for the presence of signals generated by emboli. A recent consensus committee report was published identifying criteria for Doppler-detected emboli that provide guidance for new users:I2 A Doppler microembolic signal is transient, usually lasting less than 300 ms. Its duration depends on its time of passage through the Doppler sample volume. The amplitude of a Doppler microembolic signal is usually at least 3 dB higher than that of the background blood flow signal, and depends on the characteristics of the individual microembolus. Within the appropriate dynamic range of bidirectional Doppler equipment, a signal is unidirectional within the Doppler velocity spectrum. Depending on the equipment used and its own velocity, a microembolic signal is accompanied by a "snap, " "chirp, " or "moan" on the audible output.

Diffusible Tracer Techniques The Kety-Schmidt method of inhaled nitrous oxide is the prototype for any CBF methodology involving a tracer. The ideal tracer would be physiologically inert (not affect brain blood flow or metabolism), freely and rapidly diffusible across the blood-brain barrier, and easily detected

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Figure 5. Oscillating TCD patterns from four patients that sustained traumatic brain injury with severe intracranial hypertension. Note the oscillating blood flow patterns detected by TCD. None of these patients survived. (Reproduced from Hassler W, Steinmetz H, Gawlowski J: Transcranial Doppler ultrasonography in raised intracranial pressure and in intracranial circulatory arrest. J Neurosurg 68:745,1988; with permission.)

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and quantified in blood (even better, quantifiable directly within the

133XeMethodology

Due to the relative ease in detecting and quantifying radio isotopes in blood and brain, during the 1960s 85Krand 79Krwere injected into the carotid artery to measure CBF. Instead of using tracer uptake curves to calculate CBF, as did Kety and these investigators used collimated scintillation detectors placed over the skull to generate clearance ("washout") curves for the tracers. As the radioactive tracers decay, they emit gamma rays quantitated by the scintillation detectors. Thus, the number of radioactive counts measured by the scintillation detectors correlates with the quantity of tracer within the brain. Because scintillation counts represent a composite of radioactive tracer clearances from both gray matter (higher CBF, hence, the fast component) and white matter (lower CBF, hence, the slow component), the clearance curve is mathematically deconvoluted, and fast and slow components representing different tissue compartments can be extrapolated from the raw counts (Fig. 6).,, Deconvolution is a mathematical construct that separates CBF from each of the two primary flow compartments-white and gray matter-with 133Xefrom each of the tissue compartments contributing to the total number of scintillations detected by the collimators. Because of the requirement for carotid punctures to inject the tracer, this methodology was restricted primarily to research in a few centers. A further evolution of this methodology permitted researchers to administer 133Xeby inhalation to patients. The 133Xeinhalation and intravenous injection techniques for CBF measurement have been used by numerous groups to define cerebrovascular responses to a number of clinically relevant stimuli. For example, research from the Department of Anesthesia at Bowman Gray School of Medicine revealed the relationships between arterial pCO,, CBF, and cerebral autoregulation in patients subjected to hypothermic cardiopulmonary by pas^.^^-^^ The adjustment of a hypothermic patient's pC0, to 40 mm Hg (temperature-correcting pC0, is known as pH-stat management) produces a clinically important increase in CBF than that observed in patients with alpha-stat p C 0 , management (no temperature correction used, pH-stat pC0, management produces higher for P C O ~ ) 38 . ~When ~, patient pC0, values, dilating cerebral vasculature so that CBF becomes pressure passive.39 As discussed earlier, changes in TCD flow velocities normally have a positive correlation with CBF; if flow velocity in the middle cerebral artery increases, CBF in that hemisphere increases. This relationship breaks down when conditions promoting cerebral vasospasm exist, such as after traumatic brain injury or after subarachnoid hemorrhage. Martin et a13*used simultaneous intravenous 133XeCBF and TCD measurements in victims of traumatic brain injury. They found a negative correlation between TCD velocities in the middle cerebral artery and '33Xe deter-

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Minutes Figure 6. Scintillation counts per measurement epoch (raw counts taken from detectors placed over the skull) are represented in the top curve. Dots = raw count; solid line = fitted curve; dashed dotted line = fast compartment; dashed line = slow compartment. These were measured during “washout” of inhaled la3Xe.Through the use of mathematical manipulations, the fast (gray matter) and slow components (white matter) are extracted from the raw counts. (Reproduced from Stump DA, Williams R: The regional cerebral circulation. Brain Lang 9:35,1980; with permission.)

mined ipsilateral CBF. Thus, vasospasm produced an increase in TCDmeasured velocities via the Bernoulli effect, with a simultaneous reduction in 133XeCBF measurements.32 Although this methodology has alIowed researchers to make enormous strides in the understanding of normal and abnormal brain circulatory physiology, the inconvenience and expense of radioactive tracers, and sheer bulk of the device make this methodology primarily a research tool, restricted to teaching and research institutions. Tomographic CBF Methods Stable Xe-Computed Tomography

To use this technique, patients must inhale 33% stable (nonradioactive) Xe. This is in contrast to the 133Xeinhalation technique, wherein

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less than 1%Xe is inhaled. CBF is then calculated by visualizing the Xe with computed tomography (Xe CT). This method uses Kety-Schmidt principles, and produces tomographic images of the brain with blood flow overlays. Patients are placed in a CT scanner, and a standard CT image of the brain is acquired. The patient is then allowed to breathe stable Xe, and additional CT scans are then acquired. The principle advantages of this technique are spatial resolution (localization of CBF within discrete brain areas), the use of nonradioactive Xe, and avoidance of carotid punctures. The disadvantages include anesthetic effects of Xe administered in this concentration (thus affecting blood flow) and slow scanner acquisition times (and larger radiation exposure^)^; however, evolution in technology has produced much faster CT scanners and faster microprocessors to analyze data, reducing radiation exposure.3 This technology holds promise for the rapid diagnosis of acute stroke, thereby decreasing the time needed to begin thrombolytic therapy.3s Injectable Microsphere CBF Determinations This method of organ blood flow determination is a variation of the Fick Principle, with the primary difference being that the diffusible indicator, the microspheres, do not traverse the organ. Thus, the need to use partition coefficients or to measure venous indicator concentrations is obviated. This is due to the fact that microspheres become lodged in organ capillary beds, and that the number of spheres lodged is proportional to regional organ blood flow at the time the spheres are injected. The spheres must be small enough to enter an organ's microcirculation and large enough to become firmly lodged within the organ and not recirculate (15-pm diameter spheres are commonly used). For an overview of this technique, see the reference by Warner et al.50 To actually quantitate flow, the number of spheres within a piece of tissue of known weight must be determined. This may be done in several ways. Radiolabeled isotopes are incorporated into the injectable spheres, and tissue samples containing spheres are placed in a gamma counter. By examining the number of counts emitted from a known number of spheres (acting as a standard), one can deduce the number of microspheres X gm-' of tissue that are present in any tissue sample.25 Also, one can inject colored microspheres into the subject, place the tissue samples into tissue digestion solutions, extract the spheres and count by hand the spheres in an aliquot using a Fuchs-Rosenthal hemocytometer (a laborious project), or by the use of automated counting systems.'O Blood flow to an organ can be expressed in one of two ways-first, by calculating cardiac output by another method at the time the microspheres are injected; second, by expressing organ blood flow as a percentage of cardiac output. The more commonly used method is to withdraw arterial blood at a known rate at the time the spheres are injected, with a withdrawal syringe acting as an artificial organ with known flow to it (this is known as the reference withdrawal technique).l5,25, 50 The number of spheres within the reference sample is

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determined, and from this, flows within the tissue samples of interest are determined. Because this method involves embolization of tissue (perhaps with radioactive isotopes), and the tissue of interest must be removed for flow analysis, this technique is not used in humans.

Autoradiographic Methods with Radioactive Tracers

One of the major disadvantages of some of the previously discussed methodologies is their lack of spatial resolution within the brain. Increased interest in enhanced spatial resolution has prompted the development of a method that uses a variation of the Fick principle, similar in concept to that used in microsphere determinations. This technique involves a radiolabeled diffusible tracer, such as 14C-iodoantipyrine, which is intravenously injected with simultaneous withdrawal of arterial blood. After a short circulation time of the tracer (approximately 20 seconds in the rat), the brain is frozen with liquid nitrogen.31The brain is sliced and placed on radiographic film, with the isotope exposing the film and producing an image of the brain (called an autoradiogram [Fig. 71). Brain areas with higher blood flow and greater delivery of the I4Clabeled tracer are “hotter, ” exposing the film to a greater degree. By exposing the film to known amounts of the tracer, performing densitometric analyses of the autoradiograms, and quantifying the amount of tracer in the withdrawal syringe, one may calculate regional CBF with a high degree of resolution. This method is limited by the fact that only one determination of flow can be made, radioactive substances are used, and the animal must be ~acrificed.~~

Hydrogen Clearance

This method utilizes Kety-Schmidt concepts, with the inert tracer being molecular hydrogen. Hydrogen is detected by the insertion of a platinum electrode into the tissue of interest. An electrical charge is then placed across the platinum electrode and a more distant reference electrode (the invasive nature of this method regulates it to primarily animal models). The subject is allowed to breathe hydrogen, which diffuses into tissue beds. Hydrogen in proximity to the platinum electrode is oxidized, freeing electrons, thereby generating an electrical current. The amount of current generated in this polarographic methodology is proportional to tissue hydrogen concentration, so hydrogen clearance (”washout”) curves are thus generated.52,53 From these clearance curves CBF is calculated.

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Figure 7. Autoradiograms of rat coronal brain slices. Darker areas indicate brain regions with increased blood flow. A, control animal; B, 1 minute after cortical spreading depression in the left brain. Note the increase in cortical blood flow. (L = left; R = right; c = cortex; h = hippocampus; t = thalamus.) (Reproduced from Lauritzen M, Jorgensen MB, Diemer NH, et al: Persistent oligemia of rat cerebral cortex in the wake of spreading depression. Ann Neurol 12:649, 1982; with permission.)

Positron Emission Tomography (PET), Single Photon Emission-Computed Tomography (SPECT), and Perfusion MR imaging

These three methodologies utilize different techniques to measure CBF, but share the important ability to visualize CBF in discrete brain areas. Their image spatial resolution capabilities are not equal; however, MR imaging produces significantly greater tissue resolution than those obtained from SPECT or PET (personal communication, Dr. Peter Ricci, Neuroradiology Section, Bowman Gray School of Medicine). PET utilizes radiolabeled chemicals that release positrons during their decay cycle as inert tracers. Two gamma rays are emitted 180

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degrees from one another when the released positron strikes a nearby electron, annihilating the positron, and it is these gamma rays that are captured and quantitated by collimated detectors. By placing the detectors in a ring about the head, tomographic images of the brain are generated, and the clearance of the radiolabeled tracer produces washout curves for subsequent CBF calculation^.^^ This method suffers from the expense of the device, patient exposure to ionizing radiation, and the need for a radiochemist to generate the tracers: 77Kr,18F fluormethane and 150water (150water is used most commonly in The Bowman Gray School of Medicine of Wake Forest University for PET CBF determinations; personal communication, Dr. Jenny Gage, Bowman Gray School of Medicine). PET can also quantitate brain metabolic function by using different radiolabeled ligands. SPECT methodology involves the use of radiolabeled compounds that emit gamma radiation, with collimated detectors placed in a moveable arc around the long axis of the body. By using a tracer such a~’~~X clearance e, of the isotope allows for generation of CBF data, and a tomographic representation of the brain is This methodology also requires the use of radioactive tracers, and exposes the patient to ionizing radiation. New developments in MR technology allow visualization of cerebral vasculature and cerebral blood volume. An exciting development is the use of diffusion-weighted MR scanning in acute stroke patients (which employs existing paramagnetic contrast media), producing images that appear to represent areas of brain that will eventually develop infarcts prior to the actual i n f a r ~ t i o n . ’Though ~ , ~ ~ this is not a CBF measurement technique, diffusion-weighted MR imaging may allow for more rapid and more rational application of thrombolytic therapy for stroke. The rapid acquisition of scans without need for radioactive tracers make this technology very attractive for stroke management. A recent editorial in the journal Stroke summarizes the potential utility and limitations of this technique.49An additional modification of MR imaging uses bolus administration of parametric contrast, usually Gd-diethylenetriamine pentaacetate, with transit of the contrast through the brain captured by MR imaging. From these data, regional CBF can be measured in a semiquantitative way. This technique is different from conventional MR angiography.26

CONCLUSION

In this article, the three basic concepts that provide the foundation for all CBF measurement methodologies were briefly reviewed: The Fick principle, the Kety-Schmidt variation of the Fick principle, and the Doppler effect. What followed was a brief examination of many, but not all, methods used to measure CBF in humans, laboratory animal subjects, or both.

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Address reprint requests to David A. Stump, PhD Department of Anesthesiology The Bowman Gray School of Medicine of Wake Forest University Medical Center Boulevard Winston-Salem, NC 27157-1009