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11 MEASURING CEREBRAL BLOODFLOW AND METABOLISM

Alois Zauner and J. Paul Muizelaar

11.1 Overview of CBF measurements

11.1.1 INTRODUCTION

The optimal method for measuring cerebral bloodflow (CBF) has yet to be discovered. Because of theanatomical difficulties inherent in accessing the cen-tral nervous system, quantitative measurements ofcerebral blood flow are difficult. An ideal method formeasuring CBF should provide all the following.

� Quantitative results� High spatial resolution� Continuous measurements, if clinically required� No influence on the normal brain function� No or minimal risk to the patient� Cost-effectiveness� Application in the clinical setting

The first well-recognized CBF studies on humans wereperformed by Kety and Schmidt in the 1940s usingnitrous oxide (N2O) gas. The measurement of CBF wasbased on the principle that the rate of uptake andclearance of an inert diffusible gas is proportional toblood flow. The tissue concentration of the tracer atequilibrium must therefore be dependent on bloodflow rather than diffusibility. The Kety and Schmidtequation can be used for calculating CBF using N2O,krypton-85 and xenon-133. In fact, complete equilib-rium of N2O between arterial blood, brain tissue andvenous blood occurs slowly or not at all. Thus CBFcalculated from a short saturation period will over-estimate CBF (Hoyer, 1985).

The Kety and Schmidt equation (1948) is:

C(t) = f t Ca (u)e–k(t–u)du

k = f/� = relative perfusion index (� is the partitioncoefficient of the tracer); C(t) = total amount of tracerdelivered to tissue between time zero and t; f = flow;u = tissue concentration of the tracer at time t;Ca (t) = input function, i.e. the amount of tracer

delivered to the brain, an integral of the arterialconcentration from 0 to t.

In the 1960s extracranial recordings of the uptakeand clearance of radioisotopes for measuring localCBF became available using krypton-85 and xenon-133 (133Xe; Lassen and Ingvar, 1961). Krypton-85 is aweak beta emitter and has been abandoned, whereasxenon-133, a strong gamma emitter, has been widelyused in humans. Xenon-133 is a freely diffusible inertgas that does not interfere with cerebral metabolism.Elimination occurs very rapidly and almost com-pletely through the lungs.

11.1.2 CLINICAL METHODS FOR MEASURING CBFAND BRAIN METABOLISM

Even 50 years after the first quantitative clinicalmeasurements, CBF is not routinely measured inneurosurgery or neurology. This is surprising con-sidering its potential importance in the managementof patients with severe head injury, stroke andsubarachnoid hemorrhage.

Clinical measurements of CBF and metabolism canbe divided into:

� quantitative measurements;� qualitative measurements;� indirect measurements of CBF and metabolism;� measurements of cerebral metabolism.

The most important techniques for obtaining CBF areexplained in detail below.

(a) Quantitative measurements

Quantitative CBF measurements mainly use xenon-133, either injected into a carotid artery or intra-venously, or given by inhalation (Bruce et al., 1973;Obrist et al., 1975; Agnoli et al., 1969). The stable(non-radioactive) xenon technique uses repeatedcomputer tomography scanning (Winkler et al., 1977;

Head Injury. Edited by Peter Reilly and Ross Bullock. Published in 1997 by Chapman & Hall, London. ISBN 0 412 58540 5

218 MEASURING CEREBRAL BLOOD FLOW AND METABOLISM

Got et al., 1982). Positron emission tomography (PET)for measuring CBF and cerebral metabolism is wellestablished for other purposes and is being usedmore frequently in the study of patients with severehead injury (Langfitt et al., 1986). The use of mag-netic resonance imaging (MRI) for measuring CBF iscurrently under investigation in several centers.

(b) Qualitative measurements

Qualitative CBF measurement includes single photonemission computed tomography (SPECT), laser Dop-pler flowmetry and transit time techniques usingradioactive contrast agents with CT or radioisotopeswith SPECT.

Attempts have been made to obtain quantitativeCBF values with SPECT, i.e. in ml/100 g/min, usingthe tracer 99mTC-HMPAO, but at present only thevisual interpretation of SPECT images is of clinicaluse. This may change as newer tracers are developed.SPECT may also be used to study the blood–brainbarrier after trauma (Bullock et al., 1990; Schroder etal., 1994).

Laser Doppler measures the local, relative (notabsolute) CBF in a small brain volume (1 mm3) andcan be used for tests of autoregulation and CO2reactivity (Bolognese et al., 1993).

The recently developed thermal diffusion techniqueis based on the thermal conductivity of cortical tissue,allowing continuous recordings of CBF in a smallregion of the cortex (Carter, 1991). Indirect methodsfor obtaining information on CBF and metabolisminclude jugular venous oximetry, transcranial Dopplersonography and near-infrared spectroscopy.

Continuous monitoring of jugular venous oxygensaturation (SjvO2) assesses global cerebral oxygenation.Episodes of cerebral desaturation can be detectedwhich would not been seen otherwise. Intermittentcalculations of arteriovenous oxygen difference(AVDO2) and the metabolic rate of oxygen consump-tion (CMRO2) help to determine the status of cerebraloxygen metabolism (Chapter 5; Cruz et al., 1991;Sheinberg et al., 1992).

Transcranial Doppler sonography (TCD), a non-invasive bedside test, is now more frequently used inintensive care settings (Chan, Dearden and Miller,1993; Steiger et al., 1994). Doppler sonography isdescribed in detail in Chapter 13.

Near-infrared spectroscopy (NIRS) is another non-invasive monitoring now being evaluated for itsclinical value in detecting changes in brain oxy-genation, CBF and cerebral blood volume. NIRSdepends upon the relative transparency of biologicaltissue to light in the near-infrared spectrum. Theabsorption of oxyhemoglobin, deoxyhemoglobin andoxidized cytochrome can be detected transcranially.

NIRS is most widely used to assess neonatal cerebralhemodynamics and appears reliable and useful in thissetting. In adults only certain brain areas can bemonitored because bone thickness produces a scatter-ing of the light spectrum (Elwell et al., 1993; Gopinathet al., 1993). Intracerebral microdialysis is undergoingclinical evaluation for measuring certain products ofcerebral metabolism. With this method extracellularbrain tissue electrolytes, excitatory amino acids, glu-cose and lactate can be measured (Persson andHillered, 1992; Bullock et al., 1994; Zauner and Bullock,1995). Continuous ‘on line’ pH measurements in thedialysate are also possible and need further evalu-ation. The measurement of cerebral PO2, PCO2, pH andtemperature with one fiberoptic sensor is anotherapplication still in the experimental stage that mayfind a place in managing head-injured patients (Zau-ner, Bullock and Young, 1995; Zauner et al., 1995).

11.2 Xenon CBF measurements

11.2.1 THE XENON-133 METHOD

Whatever the route of administration, this methoddepends on direct monitoring of the radioactive tracertissue concentration by external recording with multi-ple scintillation detectors placed against the scalp.Assessment of regional CBF in a number of brain areasis possible depending on the number and location ofthe detectors, but such information is not trulytomographic and it is degraded by various methodo-logical artifacts. The reader is referred to Wood et al.(Jaggi and Obrist, 1987; Ewing et al., 1987) for adetailed review.

(a) The intracarotid xenon-133 method

A bolus of xenon-133 is injected into one internalcarotid artery and the peak count rate measured byexternal detectors reflects the isotope concentration inbrain tissue. CBF can be calculated from the clearancecurve as the ‘height/area under the curve’, providingthe ‘mean’ CBF (non-compartmental index; Meier andZierler, 1954). By calculating the initial slope index afast and a slow compartment can be differentiated innormal brain. However this may not be valid ininjured brain (Risberg et al., 1975).

Over the last decade the intracarotid xenon methodhas been increasingly displaced by less invasivetechniques using inhalational xenon-133 or stablexenon-enhanced computer tomography.

(b) The non-invasive xenon-133 methods

The modified intravenous xenon-133 injection methoddeveloped by Austin et al. (1972) and the inhalation

XENON CEREBRAL BLOOD FLOW MEASUREMENTS 219

methodology developed by Obrist et al. (1975) are twoless invasive radioactive xenon techniques. In contrastto the intracarotid method, they result in greater scalpand extracerebral contamination, which needs correc-tion. Assessment of the arterial isotope input can beachieved by monitoring the xenon-133 concentrationin end-tidal air. There is a close relationship betweenend-tidal air xenon-133 and arterial concentration ifpulmonary diffusion is normal (Hausen et al., 1990).All these factors depend on a reliable mathematicalmodel for calculating CBF.

Because of the instability of compartmental analysesin patients after severe head injury, other blood flowindices, such as CBF15 and CBFinf, equivalent to theheight over area method, have been developed (Obristand Wilkinson, 1985).

In our studies, severely head-injured patients stud-ied with the inhalation method inhaled a gas mixturecontaining 5–8 mCi 133Xe/l for 1 minute. Those studiedwith the intravenous injection technique were injectedwith xenon-133 dissolved in saline (0.3 mCi/kg bodyweight). Immediately following the injection, ventila-tion was interrupted for 20 seconds to prevent largeamounts of xenon from being expired during its firstpassage through the pulmonary circulation.

After xenon-133 administration, radioactivity fromthe brain was monitored for 15 minutes (CBF15). Asystem with 16 detectors concentrically arranged in aPlexiglass helmet or a portable instrument with tenprobes may be used (Bouma et al., 1991).

For better comparison, CBF15 values are oftenrecalculated to a PaCO2 of 34 mmHg, assuming the CO2response to be 3% change in CBF per 1 mmHg changein PaCO2. Normal CBF values in young volunteerswith a PaCO2 of 34 mmHg are 44.1 ± 5.6 ml/100 g/minand increase to about 50 ml/100 g/min at a PaCO2 of40 mmHg (Obrist et al., 1984).

Advantages of this technique are quantitativeresults, repeatable measurements, a portable bedsidesystem and cost-effectiveness. The limitations of non-invasive CBF measurements are the inability to detectsmall regions of low CBF and poor spatial resolution,especially for deep brain structures.

11.2.2 STABLE-XENON-ENHANCED COMPUTEDTOMOGRAPHY

(a) Methodology

The technical limitations and the poor spatial resolu-tion of the non-invasive xenon-133 method werereasons for searching for better ways of measuringCBF with xenon as the diffusible tracer.

Sequential CT scanning allows visualization andquantification of time-dependent changes followingthe administration of a contrast medium. Winkler et

al. proposed in 1977 that the radiodensity of xenon,which is close to that of iodine, would provide CTenhancement in proportion to blood flow. Thus forCBF measurements stable non-radioactive xenon canbe inhaled during CT scanning.

Commercially available software can be easilyadded to a standard CT scanner. In studying patientswith severe head injury, good teamwork is requiredbetween neurosurgery, neuroradiology andintensivists.

CBF is computed by measuring the brain tissueuptake during arterial build-up of xenon. The end-tidalxenon concentration is assumed to be in equilibriumwith the concentration in arterial blood. Subsequently,the time-dependent change in arterial xenon concen-tration is obtained and can be converted to equivalentCT units (Obrist et al., 1975). Additionally, a correctionfor the hematocrit is required. The relationship for thehematocrit is shown in the following equation:

Ca(t) = kXe(t) (1 + 1.1 hct)

Ca(t) = arterial xenon concentration; k is a conversionconstant; Xe(t) = end-tidal xenon concentration; hct =hematocrit.

The baseline images are averaged and subtractedfrom the enhanced images obtained during xenoninhalation, producing a sequence of raw enhancedimages. CBF is calculated by using the Kety andSchmidt equation on a pixel by pixel basis (Kety andSchmidt, 1948). CBF images are generated by com-puted flow values which are converted into Houns-field units. Software post-processing techniques andsmoothing procedures reduce image artifacts. A con-fidence image for each CBF image yields informationabout the quality and reliability of the CBF assess-ment. Most centers use 6–12 minute xenon washinprotocols for calculating CBF (Bouma et al., 1991; Got,Yonas and Good, 1989; Good, Got and Yonas, 1992;Nakano et al., 1992). Xenon washin and washout(clearance) protocols have the advantage of capturingmore data points, which increases the accuracy ofblood flow measurements and a shorter inhalationtime of xenon. Fatouros et al. showed that a 3 minuteswashin, i.e. 3 minutes of xenon inhalation only, and 3minutes washout procedure is superior to 6 minuteswashin alone, especially if low blood flow is present(Fatouros et al., 1995a).

(b) Clinical studies

At the Medical College of Virginia, CT-CBF measure-ment for severely head-injured patients (GCS 8 or less)is a routine diagnostic procedure. The first CBF scan isusually performed on admission following a regulardiagnostic head scan, unless the patient is clinicallyunstable or needs the immediate evacuation of a


hematoma or any other emergency surgical treatment.Prior to CT-CBF scanning, arterial blood gas analysisand hematocrit are required. To avoid artifacts, thepatient must not move during the study and sedationand/or muscle paralysis may be necessary . At presentan 8 minute xenon washin study is performed. Asnoted above, a 3 minute washin and 3 minute washoutprotocol is currently being investigated. Two baselinenon-enhanced scans are obtained at three levels of thebrain determined from the diagnostic CT scan. A gasmixture containing 30% xenon and 30–60% oxygen isthan delivered for 8 minutes via a specially designedenhancer connected between the respirator andpatient. Eight sequential CT scans at each level areobtained during the 8 minute period using a rapidsequence CT technique. Xenon end-tidal values areobtained and recorded during the study. End-tidalPCO2 is measured with a capnograph and O2 satura-tion is monitored using a pulse oximeter. Bloodpressure and intracranial pressure may be continu-ously monitored throughout the study and in somepatients transcranial Doppler measurements are alsoperformed prior to or during the study. CBF studiesadd about 15–30 minutes to a regular CT scan. Follow-up CBF studies are performed between days 3 and 5 oras needed, to distinguish brain ischemia from hyper-emia. Depending on the clinical situation cerebralblood volume (CBV) may also be measured byinjecting 50 ml iodinated non-ionic contrast materialintravenously after completing the xenon study. CBVis calculated by multiplying CBF by the mean transittime (MTT) for contrast (see below). CBF images areanalyzed according to regions of interest (ROI) imme-diately after the measurements. Hemispherical orregional values are calculated by outlining thesestructures using drawing tools on the CT screen.

(c) Advantages and limitations of the stablexenon technique

Quantitative, non-invasive blood flow measurementsin the superficial cortex as well as in deeper structures,such as brain stem and basal ganglia, can be studied.The direct correlation with anatomy on the baselineCT images enables easy recognition of specific regionsof interest. Problems associated with the xenon-133technique, such as extracerebral contamination andthe ‘look-through phenomenon’ do not occur with thistechnique. Added to a regular CT scan, it can beundertaken in severely head-injured patients withoutputting them at risk, although careful monitoring ofblood pressure, O2 saturation, ICP and end-tidal CO2is necessary.

There are several reports of the direct effects ofxenon inhalation on CBF and ICP. At greater than50% concentration, xenon is an anesthetic agent and

may cause respiratory depression and cerebral vaso-dilation thereby increasing ICP (Bruce et al., 1973;Giller, Purdy and Lindstrom, 19990; Takasago et al.,1992; Obrist, Jaggi and Harel, 1985; Winkler andTurski, 1985). By using shorter xenon inhalationtimes (washin and washout procedures) and a max-imal xenon concentration of 32%, a compromise canbe achieved between xenon side effects and accuracy– which depends on sufficient enhancement for agood signal-to-noise ratio. The radiation exposure ofapproximately 8–28 cGy per studied level must bealso considered (Good, Got and Yonas, 1992). In anawake or agitated patient head motion is anotherlimitation, whereas in the comatose head-injuredpatient, with proper sedation and head fixation, thisis usually not a problem.

(d) Cerebral blood volume (dynamic CTtechnique)

In patients with severe head injury, cerebral bloodvolume (CBV) is of great interest, especially if ICP israised as a result of brain edema and/or vascularengorgement. Increased CBV may accompany high,normal or low CBF, suggesting that CBF and CBV arenot simply related (Grubb et al., 1978; Muizelaar etal., 1989; Phelps et al., 1979). The ratio of CBF/CBVmay help to differentiate between irreversible andreversible ischemia in some patients (Leblanc et al.,1987; Powers and Raichle, 1985).

With CT scan times of 2 seconds and very shortinterscan delays it is possible to assess the kinetics ofthe first passage of an i.v. bolus of iodine contrastthrough brain tissue. The mean transit time (MTT) ofthe bolus through the cerebral vasculature can then beestimated and CBV be calculated as CBV =CBF � MTT.

The MCV method is manually to inject a bolus of50 ml of iodinated non-ionic contrast medium throughan i.v. line in less than 5 seconds. The hemispheres orany other regions, excluding major vessels and theventricular system, may be chosen as ROIs and themean Hounsfield number in each region is calculated.The CT enhancement versus time curves are fitted to agamma variate function:

C(t) = k(t – ta)�e– (t - ta)/�

where t = time after injection; ta = indicator appear-ance time; k, �, � are fit parameters; C(t) = indicatorconcentration that is proportional to the CT number.

The arrival time, as well as a cut-off point on thedownslope to avoid recirculation, must be specified bythe operator or computed automatically. The use of agamma variate function greatly simplifies the compu-tation of the MTT. The interval between the first andsecond inflection points, which is the inflection width

FURTHER DIRECT CLINICAL METHODS FOR OBTAINING CBF 221

(IW) of the time density curve can be used as anestimate of MTT. The IW represents the transit time ofthe densest part of the bolus and this is close to theMTT (Axel, 1980; Oldendorf, 1964; Bouma et al., 1992;Fatouros et al., 1995b).

In summary, a CT-based method for measuring CBVis practicable, by combining CBF measurements withthe stable xenon CT technique and using the inflectionwidth following an intravenous iodine bolus as thecerebral transit time. However, additional work isrequired to further validate this method.

11.3 Further direct clinical methods forobtaining CBF

11.3.1 THERMAL DIFFUSION TECHNIQUE

The thermal diffusion measurement of cortical CBF(CoBF) is based on the thermal conductivity of corticaltissue (Carter et al., 1982; Dickman et al., 1991). Asensor consisting of two small flat gold plates, one ofwhich is neutral and the other heated, is placedthrough a burr hole or craniotomy on a region ofinterest of the cortex. The CoBF in ml/100 g/min isestimated from the temperature difference betweenthese two plates. If CoBF increases, the temperaturedifference between the two plates becomes smaller,the heat loss being conducted through the capillarybed. A microprocessor continuously converts thetemperature difference to CBF in ml/100 g/min.Placement of the sensor over large surface vesselsshould be avoided.

Cortical blood flow measurements have been usedin patients following subarachnoid hemorrhage andhead injury, as well as after surgery for tumors,arteriovenous malformations or epilepsy (Carter, 1991;Carter et al., 1982; Dickman et al., 1982). In head-injured patients, continuous monitoring of CoBF mayassist in differentiating cortical ischemia from hyper-emia, and permit autoregulation and CO2 reactivitytests to be done. Hyperventilation during increasedICP may be monitored with less risk of inducingischemia. A correlation between CoBF and wholebrain CBF measured by the Kety and Schmidt N2Omethod has been shown (Carter, Weinand and Oom-men, 1993; Robertson, 1993). Although CoBF is notrepresentative of blood flow in the whole hemisphereor in deeper regions of the brain, continuous measure-ments of relative changes in the days after severe headinjury may be of great value in guiding clinicalmanagement.

11.3.2 LASER DOPPLER FLOWMETRY

Laser Doppler flowmetry (LDF) is a new method forcontinuous measurement of local microcirculatory

blood flow. The method is based on the principle ofDoppler shift (Chapter 13). Monochromatic laser lightreflected from stationary tissue remains unchanged infrequency. When it is reflected from moving bloodcells it undergoes a frequency shift and therefore lightreflected from the microcirculation measures themovements of red blood cells (Frerichs and Feuerstein,1990; Meyerson et al., 1991). Monochromatic laserlight, wavelength 600–780 nm, which is above themaximal absorption of hemoglobin and below theabsorption of water, is used. The magnitude andfrequency distribution of the wavelength changes aredirectly related to the number and velocity of redblood cells but unrelated to the direction of theirmovement. The light is carried by a fiberoptic probeand the reflected light is converted into an electricalsignal from which several values are derived. The flux(an arbitrary flow unit) represents the movement andconcentration of blood cells through the microvascu-lature. It is derived from the concentration of movingblood cells (CMBC) in the measured volume multi-plied by the mean velocity. All three values, flux,CMBC and velocity, are continuously recorded andcan be displayed by a computer (Bolognese et al.,1993). Absolute CBF in ml/100 g/min can be theoret-ically estimated from LDF measurements, but must beinterpreted with great caution. LDF measures thelocal flow within a very small sample volume ofapproximately 1 mm3, depending on the type of laserbeing used, and varies markedly with the location ofthe probe and its relationship to the microvasculature(Meyerson et al., 1991; Haberl, Villringer and Dirnagl,1993). At present the measurement of relative valuesand their changes over time seems to be more accuratethan relying on absolute values.

LDF has been developed for bedside monitoring(Meyerson et al., 1991; Bolognese et al., 1993) andrequires surgical implanting. The device may be usedalone or with other intracranial monitoring devices(Meyerson et al., 1991; Bolognese et al., 1993; Haberl,Villringer and Dirnagl, 1993; Steinmeier, Bondar andBauhuf, 1993). In patients with severe head injury,LDF can be used to assess CO2 reactivity and the stateof autoregulation (Le Bihan and Turner, 1992).

11.3.3 MAGNETIC RESONANCE IMAGING FOR CBFMEASUREMENTS (CHAPTER 14)

The washin and washout kinetics of exogenouslyadministered MRI-detectable tracers, such as2H-water, 19F-trifluoromethane and gadolinium per-mit measurements of cerebral perfusion (Zhang, Wil-liams and Koretsky, 1993). Most of these tracers arestill under investigation and MRI studies for calcu-lating CBF in acute clinical settings such as head injuryare not yet possible.


Recently a technique for proton magnetic resonanceimaging (MRI) has been developed using water as thefreely diffusible tracer. This technique involves label-ing the water proton nuclear spins in the arterial bloodby continuously inverting them in the neck regionbefore they enter the brain. This permits the calcula-tion of CBF (Williams et al., 1992). Le Behian et al. havetaken another approach for calculating CBF (Le Bihanand Turner, 1992). They have focused on the capa-bility of magnetic resonance to image and measuremolecular diffusion and capillary blood flow orperfusion. By using diffusion imaging techniques,perfusion can be measured non-invasively on thebasis of intravoxel incoherent motion (IVIM). ThisMRI model considers that capillary segments arerandomly oriented in each voxel and the perfusionseen by the IVIM technique is quantified in terms ofactive capillary density or average blood flow velocityrather than as ml/100 g/min.

At present for patients with severe head injury CBFmeasurements using MRI are in an experimentalstage, but MRI has great potential and warrantsfurther exploration.

11.4 Indirect methods for obtaining CBFand metabolism

11.4.1 JUGULAR VENOUS OXIMETRY

Jugular bulb oxygen saturation can be used tocalculate AVDO2 and to monitor cerebral oxygenation.The cerebral metabolic rate for oxygen (CMRO2) canbe calculated as:

CMRO2 = CBF � AVDO2.

Under physiological conditions CBF and CMRO2 arecoupled and the ratio of these two parameters, andAVDO2, remains constant (Robertson et al., 1989). Thenormal value for AVDO2 is approximately 6.5 mlO2/100 ml blood and for CMRO2 3.2 ml O2/100 g/min(Muizelaar and Schroder, 1994). In about 45% ofpatients who are comatose following severe headinjury, CMRO2 and CBF remain normally coupled(Obrist et al., 1984). Only in these patients does a highAVDO2 indicate low CBF relative to CMRO2, as thebrain compensates for the decreased CBF by extract-ing a greater amount of oxygen, and conversely a lowAVDO2 indicates increased CBF (Robertson et al.,1989). Cruz has suggested that measuring the cerebraloxygen extraction, i.e. the difference between arterialand jugular bulb oxyhemoglobin saturation, is moreaccurate than AVDO2, especially in the presence ofanemia (Cruz, 1993a).

Fiberoptic catheters that measure jugular venousoxygen saturation (SjvO2) continuously in the jugularbulb are a major advance over intermittent jugular

monitoring (Cruz, 1993a, b; Sheinberg et al., 1992). Ano. 4 or 5G fiberoptic oxygen saturation catheter isinserted percutaneously in a retrograde direction intothe internal jugular vein. The tip of the catheter mustbe placed within the jugular bulb and its positionverified by X-ray or CT-scan. The catheter must becalibrated before and after insertion and thereafterevery 8 hours by drawing a blood sample from thecatheter and measuring the oxygen saturation on aco-oximeter. The reflected light intensity of the fiber-optic device must be checked regularly. It depends oncorrect placement of the catheter tip within thelumen and will be reduced if the catheter becomesattached to the vein wall. SjvO2 in normal individualsis 65%. However, in comatose patients with severehead injury, readings over 50% are considered nor-mal (Sheinberg et al., 1992). An SjvO2 less than 50%and AVDO2 above normal indicate ischemia or amismatch between CBF and metabolism. Becausearterial oxygen saturation and arterial hemoglobinaffect cerebral metabolism and oxygenation, theymust also be taken into consideration (Cruz, 1993a,b). Whenever SjvO2 drops below 50% for more than15 minutes, the cause of the desaturation must besought. First, the light intensity of the cathetershould be checked and the catheter calibrated by co-oximeter. If both are within the normal range thencerebral desaturation has occurred. Episodes of cere-bral desaturation occur most frequently within thefirst 48 hours after injury, most often in relation tohigh ICP (Muizelaar and Schroder, 1994; Sheinberg etal., 1982).

There are several limitations with jugular bulboximetry.

� It measures the global saturation of one hemisphereonly.

� SjvO2 may not decrease during raised ICP untiltentorial herniation has occurred (Sheinberg et al.,1982).

� There is contamination with blood from the con-tralateral hemisphere and from extracranial venousblood.

A previous study found that almost 50% of readingsthat suggested desaturation were incorrect (Sheinberget al., 1982), usually as a result of low light intensity.

At present jugular venous oximetry is the onlymethod available to give continuous monitoring ofcerebral oxygenation and metabolism. Even thoughthe technique can be time-consuming, several authorshave found it helpful in management, even thoughexperience at the Medical College of Virginia has, incomparison, been disappointing. In the near futurecerebral tissue O2 and CO2 measurements may proveto be a better way of monitoring comatose patients(Zauner and Bullock, 1995; Zauner et al., 1995).

DIRECT MEASUREMENT OF CEREBRAL METABOLISM 223

11.4.2 TRANSCRANIAL DOPPLER SONOGRAPHY

Transcranial Doppler sonography is discussed indetail in Chapter 13.

The technique was introduced in 1982 by Aaslid,Markwalder and Nornes (1982). Using a 2 MHzpulsed Doppler it is possible to penetrate the skull atcertain areas and to record the blood flow velocityfrom the major basal cerebral arteries. The mostfrequent measurement site is transtemporal (via the‘temporal window’), where the middle cerebral artery,internal carotid artery and anterior cerebral artery canbe identified (McCormick et al., 1991). Vessel identi-fication depends on the cranial window used, thedepth of the sample volume, the flow direction andthe spatial relationships of vessels. The vertebralarteries and the basilar artery may be insonatedthrough the foramen magnum.

A standard nomenclature has become accepted, inwhich peak systolic velocity refers to the highestvelocity during systole and the end-diastolic velocityrepresents the maximum velocity at the end of thediastole. The mean velocity is the time averagedmaximum velocity during the cardiac cycle.

Blood flow velocity does not give direct informa-tion on CBF. In an artery with a lumen area A (cm2),the blood flow Q (ml/s) and cross sectional averageblood velocity V (cm/s) are related by the followingequation:

Q = VA.

However cross-sectional blood velocity is difficultto measure, since the anatomy of cerebral arteries isvery complex. Blood flow velocity is further influ-enced by several factors, including arterial bloodpressure, ICP, hematocrit, PaCO2 and the status ofautoregulation, thus making a direct comparison offlow velocity and CBF very complex. All these factorsmay be altered in severe brain injury and may makeDoppler measurements difficult to interpret (Steiger etal., 1994).

11.4.3 NEAR-INFRARED SPECTROSCOPY

Near-infrared spectroscopy (NIRS) was recentlydeveloped as a continuous bedside technique suitablefor clinical use particularly in neonates. Near-infraredlight with a wavelength between 650–1100 nm canpenetrate the scalp, skull and brain (Jobsis, 1977;McCormick et al., 1991). Penetration into brain tissue islimited by the thickness of the skull. In adults itextends for a few centimeters only, whereas inneonates penetration is much deeper. Thus relativechanges in CBF and cerebral oxygenation can beinvestigated transcranially by means of the transpar-ency and absorption of oxyhemoglobin, deoxyhemo-globin and oxidized cytochrome in the near-infrared

spectrum. The absorption of hemoglobin occurs at awavelength between 670 and 760 nm, whereas oxi-dized cytochrome aa3 is detected near 830 nm. Noseparation into arterial, venous or capillary compart-ments in the measured brain areas can be discerned.Recent studies in adults have reported that NIRS is atleast as sensitive in detecting progressive humancerebral hypoxia as EEG (McCormick et al., 1991).Gopinath et al. (1993) have also found NIRS useful indetecting and localizing intracranial hematomas.Potential limitations of this application are that onlyacute hematomas could be found and that bilateralhematomas might not be detected.

With further refinement NIRS may prove to beuseful in managing patients with severe head injury inthe intensive care unit or the emergency room, both todetect brain oxygen desaturation in selected areas andlocalize intracranial hematomas. At present, NIRS ismore reliable in neonates than in adults.

11.5 Direct measurement of cerebralmetabolism

11.5.1 INTRACEREBRAL MICRODIALYSIS

Intracerebral microdialysis enables endogenous sub-stances in the extracellular fluid (ECF) of the brain tobe retrieved. Many experimental studies have sug-gested that excitatory amino acids (EAAs), neuro-transmitters, electrolytes and energy-related metabo-lites are released in abnormal quantities after severehead injury. EAAs such as glutamate and aspartatehave toxic effects on cell membranes and cause celldamage particularly in states of prolonged ischemia(Ungerstedt, 1991; Beneviste and Hiittemeier, 1990).The membranes of microdialysis probes in current usehave a length of 4–10 mm and a diameter of 0.5 mm.They may be implanted during surgery or togetherwith an ICP monitoring device (Persson and Hillered,1992; Bullock et al., 1994). The probe is perfused withsterile normal saline or Ringer’s solution using amicroinjection pump (2 �l/min). The dialysate iscollected in vials over a defined interval (for example:30 min = 60 �l) in a cooled fraction collector. In ourstudies the probe is left in place for 4 days. Thesamples are analyzed by high performance liquidchromatography for EAAs, lactate and glucose, andby flame photometry for electrolytes (Bullock et al.,1994, 1995; Zauner and Bullock, 1995). In the first 50patients with severe head injury, there was a six- toeightfold increase in EAAs if there were no secondaryischemic events. However, if secondary ischemiaoccurred, EAA release was 20–50 times greater thannormal and persisted over days (Figure 11.1; Perssonand Hillered, 1992; Bullock et al., 1994, 1995; Zaunerand Bullock, 1995). An increase in ECF K+ following


severe head injury was also seen and correlated withthe increase of glutamate. In ischemia, a rise in ECF K+

and an influx of Ca+ is thought to trigger glutamaterelease and activation of cation and anion conduct-ance. (Bullock et al., 1995). A marked reduction in ECFglucose can be seen after head trauma. This is mostprobably due to low CBF and increased anaerobicmetabolism (Figure 11.2).

11.5.2 POSITRON EMISSION TOPOGRAPHY

Positron emission topography (PET) scanning is cur-rently the most versatile and widely used functionalimaging modality for the human brain, both in healthand disease. The theory and methodologies of thetechnique are beyond the scope of this chapter and thereader is directed to Alavi et al., 1982, 1996; Huang etal., 1980; Phelps, Mazziotta and Huang, 1982; and

Heiss et al., 1984. However, in spite of the enormouscost and complexity of PET scanning, it has made littleimpact on either research or clinical practice in theneurosciences. Since the isotopes must be obtained on-line from a cyclotron, PET scan studies need to beplanned and scheduled well in advance. Patients needto be stable and in close physical proximity to thescanner and this limits its utility in patients with acutehead injuries. The anatomical resolution of detail isquite limited, being about 0.5 cm3, which is similar tothat of SPECT scans.

Despite these limitations, the technique has beenapplied to studies in patients with head injury. CBFand metabolism were studied in stable patients duringthe first and second weeks after head injury(Langfitt etal., 1986). There were uniform reductions in both CBFand metabolism, the most profound reductions beingfound in the parietal and occipital lobes. More

(a) (b) (c)

(d) (e)

Figure 11.1 (a–c) Regular CT scan and xenon cerebral blood flow images. The regular scan (a) shows a subdural hematomaoverlying the left hemisphere in a patient who later died. Regions of interest can be drawn and projected on thecorresponding xenon images to calculate local (b) or hemispherical (c) blood flow. In this particular patient, flow wasapproximately 6 ml/100 g/min at the time of the study. (d, e) Regular CT scan (d) and xenon cerebral blood flow images(e) in a patient with favorable outcome. Hemispherical blood flow reached approxiamtely 27 ml/100 g/min. A region ofinterest is drawn in the area of placement of a microdialysis probe (for measuring glucose, lactate, amino acids and ions) anda multiparameter sensor (for measuring brain PO2, PCO2, pH and temperature; see section 11.6 for further detail) to correlatecerebral blood flow with these data. The blood flow in the region of interest is shown in the right upper corner of the flowimage (24.2 ml/100 g/min).

DIRECT MEASUREMENT OF CEREBRAL METABOLISM 225

recently, elegant studies of glucose metabolism usingfluorodeoxyglucose found that in about one-third of13 patients cerebral metabolism for glucose wasincreased within 48 hours of injury. The greatestincreases were seen in zones surrounding focal cere-

bral contusions and adjacent to hematomas (Hovda etal., 1995). These findings accord exactly with animalstudies. At later time points, however, glucose metab-olism had decreased by 30–40%, also in accord withfindings in animal studies. It appears, therefore, that

Figure 11.2 Methods of placement of a microdialysis probe.

Figure 11.3 Instrumentarium used for placement of a triple lumen bolt (drill bit, taper), together with the multiparametersensor, microdialysis probe and triple lumen blot itself.


there is a initial phase of hypermetabolism for glucoseafter trauma, which is followed by a phase ofhypometabolism. The potential of PET scanning todemonstrate changes in neurotransmitter metabolismand protein synthesis has yet to be fully realized.

11.6 Comprehensive neuromonitoring

There are now a number of monitoring and diagnosticdevices that have been developed for use in comatosepatients. They include devices for ICP monitoring,jugular bulb oximetry, CBF measurement, transcranialDoppler sonography and EEG. However none of thesetechniques is ideal, and only indirect information oncerebral oxygen delivery and metabolism can beobtained from them.

At the Medical College of Virginia, a comprehensiveneuromonitoring system is being developed thatincludes an ICP monitor with a microdialysis probeand a combined sensor for measuring brain oxy-genation, CO2 generation, and temperature (Zauner,Bullock and Young, 1995; Zauner et al., 1995) With thissystem it is possible to continuously measure ICP,CPP, brain oxygen, CO2, pH and temperature, as wellas brain chemistry for glucose, lactate, ions and aminoacids, for several days after injury (Figure 11.3). Thethree measuring devices are secured to a three lumenbolt for skull and brain fixation. This system is beingassessed in patients with severe head injury butfurther work is needed to establish its value inintensive care management.

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