Review of the measurement of normal spinal cord blood flow

Brain Research, 118 (1976) 181-198

181

© Elsevier/North-HollandBiomedicalPress, Amsterdam- Printed in The Netherlands

Review Article

REVIEW OF THE MEASUREMENT OF NORMAL SPINAL CORD BLOOD FLOW

ALAN N. SANDLERand CHARLESH. TATOR Medical Sciences Building, Room 7317, University of Toronto, Toronto, Ontario, MSS 1A8 and Sunnybrook Medical Centre, Toronto, Ontario, M4N 3M5 (Canada)

(Accepted April 13th, 1976)

SUMMARY The field of spinal cord blood flow (SCBF) is reviewed. The methodology currently being used to evaluate SCBF is critically analyzed. The review demonstrates that there is a paucity of reliable quantitative measurements of SCBF. The effects of arterial pCOz, pOz and blood pressure variations as well as the effects of several pharmacological agents on SCBF are also discussed.

INTRODUCTION There has recently been a rekindling of interest in the field of spinal cord blood flow (SCBF) because recent work in experimental cord trauma has renewed the longstanding controversy about the effect of cord trauma on SCBF. This paper critically reviews the methodology and results of studies on SCBF. It will be evident to the reader that in contrast to the field of cerebral blood flow, relatively few studies exist on SCBF. In fact, only recently have the advances and improvements of the cerebral blood flow field been applied to the spinal cord. Although several methods have been used to study normal SCBF, only 7 have provided quantitative data. The other methods have been non-quantitative and have provided only a limited amount of information. The quantitative studies are listed in Table I and will be discussed in detail. Then, the non-quantitative methods will be briefly described. ( A ) Quantitative studies

All of the available techniques for the quantitative measurement of organ blood

182 flow require either the sampling of uncontaminated venous blood or the measurement of the quantity of the tracer contained in the organ. The latter is measured at either one particular time, as in tracer uptake studies, or over a period of time, as in tracer washout studies. The small size and complexity of the venous drainage of the spinal cord prevent the use of venous sampling techniques, and thus the techniques used to quantitate SCBF involve either tracer uptake or tracer washout and the measurement of the quantity of the tracer in the cord. In 1955, Landau e t al. 4v performed the first quantitative study of SCBF. They used an inert radioactive gas, tri-fluoro-iodomethane labeled with a31I (CF3131I), and an autoradiographic technique to measure regional blood flow in the central nervous system. The theoretical basis for the use of inert diffusible substances to measure local blood flow has been extensively reviewed by Kety a9 and all quantitative techniques for the measurement of SCBF are based on the Fick principle 21. The tissue concentrations of a biologically inert gas abruptly introduced into the arterial blood depend upon the gas solubility in tissue and blood, the history of the gas concentration in the arterial blood, and the tissue circulation. Landau et al. 47 injected CFa13~I intravenously and monitored the arterial concentration with a scintillation counter. The gas concentrations in various regions of the central nervous system were measured densitometrically from autoradiographs of frozen tissue slices 1 min after the start of the intravenous injection. They found that the cervical spinal cord white matter in awake, unrestrained cats had a blood flow of 14 ml/100 g/min and grey matter had a flow of 63 ml/100 g/rain. This was an excellent method and provided values for regional blood flow in the spinal cord. In fact, the autoradiographic method was the first method to provide accurate differentiation between grey and white matter blood flow 26,47. Sandlet and Tator ~6 have measured SCBF in primates using the [14C]antipyrine autoradiographic technique developed by Reivich et al. 55 to measure cerebral blood flow. Thoracic white matter SCBF was 10.3 ml/100 g/min and grey matter SCBF was 57.6 ml/100 g/min. Very high resolution of SCBF in cord cross-sections was achieved with the autoradiographic method. For example SCBF in areas of the cord such as the dorsal columns, pyramidal tracts or anterior horns of the grey matter could be easily differentiated. Fig. 1 shows the excellent resolution of SCBF which can be achieved with this technique. With this method, the cord is not traumatized by the insertion of probes, needles or electrodes as is required by most of the other quantitative methods used to measure SCBF as discussed below. In addition flow can be measured in discrete zones of the whole cross-sectional area of the cord each time. A disadvantage of the method is that the animal must be sacrificed at the time of SCBF measurement so that the tissue can be prepared for autoradiography. Therefore, to study the time course of changes in SCBF produced by trauma or other conditions, groups of animals must be sacrificed serially. It is acknowledged that the use of [14C]antipyrine to measure blood flow in the central nervous system has been criticized by Eckman et al. 14 who have compared experimentally derived flow values using either [laC]antipyrine or CFa131I against theoretically derived flow values generated for a systematically varied range of blood

183

Fig. 1. Autoradiograph showing normal primate SCBF. The darker the area, the greater the blood flow. Differentiation between grey and white matter SCBF can be easily made. The numbers depict SCBF in ml/100 g/rain for the areas outlined. flow and capillary permeability values using a digital computer. Errors in the calculated flow values were greatest for high rates of blood flow and low permeability coefficient-surface area products. The authors concluded that [14C]antipyrine uptake into the cat brain was limited by both blood flow and capillary permeability and that it was unwise to use [14C]antipyrine for the measurement of regional cerebral flow under conditions in which increased flow was being measured. However, Ekl6f et a116 have also evaluated the accuracy of cerebral blood flow measurements using several tracers including [14C]antipyrine, [14C]ethanol, [~H]water and 188Xenon substituted for N2015. For [14C]antipyrine at normal pCO2 levels using the same 60 see infusion period as we used, cortical flow was 90 4- 5 ml/100 g/min whereas using the K e t y Schmidt technique cortical flow was 100 4- 3 ml/100 g/rain. As the thoracic SCBF in the grey matter in our experiment was less than 100 ml/100 g/rain, Ekl~f et al.'s results support our view that [14C]antipyrine provides accurate values for SCBF. The ~33Xenon washout method has been used by 3 groups of investigators (Table I). In 1969 Smith et al.n0 measured blood flow in the goat spinal cord at the thoracolumbar junction by injecting 2/~1 of 133Xenon in saline into the spinal cord using a 29-gauge needle inserted 4--6 mm below the cord surface. The tissue clearance of laaXenon was then monitored with a crystal scintillation probe placed 1 mm above the cord surface and blood flow estimated from the clearance curve obtained. It was not

7. Particle distribution method

5. Argon washout + intracord vacuum mass spectrometer probe 6. Hydrogen clearance

Flohr et al. 2a-2~

(b) Griffith et al. 3z

(a) Kobrine et al. 45,46

Ducker and Garrison 7

(c) Griffiths28

(b) Ducker and Perot 1° 13

(a) Smith et al. 8°

Bingham et al. 1

3. [x4C]antipyrine indicator fractionation technique

4. laaXenon washout

Primates, thoracic Primates cervical

Sandier and Tator 56

2. [14C]antipyrine uptake ÷ autoradiography

Dogs, segment not given Baboons, segment not given Cats, cervical thoracic lumbar

Primates, thoracolumbar Rhesus monkeys, thoracic

Goats, thoraco-lumbar Dogs, thoraco-lumbar Dogs, thoracic

Lumbar

Thoracic

Cats, cervical

Species and cord segment

Landau et al. 47

Authors

1. Tri-fluoro-iodomethane (CFa la1I) uptake q- autoradiography

Method

Quantitative studies of normal spinal cord blood flow

TABLE I

White matter Grey matter White matter Grey matter White matter Grey matter White + grey matter White + grey matter White T grey matter

White ÷ grey matter

White matter Grey matter

White + grey matter

White + grey matter

White matter Grey matter White matter Grey matter White matter Grey matter

White matter Grey matter White matter Grey matter

SCBF ml/ lO0 g/min

17.5 14.0 11.5 10.8 13.7 16.5 20.3 16.5 23.7

15.0

15.7 48.4

15.6

16.2

19.7 48.4 13.9 40.6 21.7 43.7

14.0 63.0 10.3 57.6

185 possible to deliver the zaaXenon to the spinal cord via the arterial system because the radicular arteries went into spasm with minimal manipulation. Furthermore, isolation of the cord from surrounding tissues could not be achieved when large quantities of z38Xenon were injected into the descending aorta. Thus the z83Xenon clearance technique was adopted. In contrast, cerebral blood flow studies with z38Xenon are more easily performed because the tracer can be injected into the carotid arteryBe. The main disadvantages of this technique are the possibility of cord damage from the injection, and the uncertainty about the exact site of injection. Histological studies of 2 cords in which ink was injected showed no disturbance of normal cell architecture, and therefore the authors concluded that their method was acceptable. In support of their argument is the study of cord intramedullary microinjection by Sinha et al. 59 who found that small volumes of methylene blue did not damage the cord and stated that the results obtained with intramedullary injection of 183Xenon corresponded to that seen with methylene blue. The other major disadvantage of the xa3Xenon microintramedullary method of SCBF measurement is the uncertainty concerning the exact site of injection, i.e., grey matter alone, white matter alone or both. In an attempt to identify the actual site of injection, 2 #1 of India ink was injected into the spinal cord of 2 of the goats at the end of the procedure in the same manner as the 133Xenon was injected. The India ink was found in both grey and white matter, and thus the flow values obtained were regarded as indicating flow in a composite of both grey and white matter. The mean value for all their measurements at normal pCO2 levels was 16.2 ml/100 g/min. A further problem with the method concerns the partition coefficients for zaSXenon. A knowledge of the partition coefficients between the spinal cord tissues and blood is required for the calculation of SCBF. Veall and Mallett64 have shown that the partition coefficients for Xenon between brain and blood are different for grey matter and white matter. However, Smith et al. 60 were unable to use these values for the partition coefficient due to the unknown amounts of grey and/or white matter into which the z33Xenon was injected. To obviate this problem they chose a value of unity to represent the partition coefficients for both grey and white matter. They acknowledged that this assumption may have resulted in an overestimation when white matter may have received most of the injectate and an underestimation of flow when grey matter may have received more 133Xenon. In addition, although the clearance curves for z38Xenon obtained from the spinal cord could usually be resolved into two exponential components, Smith et al. 6° concluded that these components did not represent the flow in grey matter and white matter, respectively. In contrast when cerebral blood flow is measured after intracarotid injection of 183Xenon86 it has been customary to attribute the two components to flow in grey and white matter, respectively. However, Ingvar and Lassen3v have observed multicomponent decay curves after intracarotid injection of SSKrypton which measures cortical blood flow only since SSKrypton is a weak fl-emitter. This demonstration of decay curves which were not monoexponential in grey matter provided the basis for Smith et al.'s e° decision not to differentiate the two components they observed in their decay curves into grey and white matter flow. Ducker and Perot 10-z3 also used the z33Xenon clearance technique to measure

186 SCBF in the lower thoracic and upper lumbar cord segments in dogs, and they too were unable to ascribe the values obtained to grey or white matter. At normal blood gas tension they found the mean 'cord' flow to be 15.6 ml/100 g/rain. It is interesting to note that these 'cord' flow values found by Smith et al. 6° and Ducker and Perot r°- la of 16.2 and 15.6 ml/100 g/min, respectively are similar to the white matter flow values determined by Landau et al. 47 and Sandier and Tator 56 with the autoradiographic technique. This makes it very likely that the 133Xenon injections made by these two groups were primarily into white matter. In support of this is the fact that there is relatively much more white matter than grey matter in the thoracic cord segments they studied. Griffiths 28 in 1974 also used the r33Xenon method to measure SCBF in dogs between T12 and L4, but in contrast to Smith et al. ~° and Ducker and Perot 10-~a, Griffiths 2s concluded that he could measure flow in both white and grey matter. He concluded this on the basis that the desaturation curves were biexponential in approximately 40 ~ of the measurements. In these instances the slow component was taken to represent white matter flow and the fast component was taken to represent grey matter flow. In the other 60 ~ the clearance curves were monoexponential and these were taken to represent white matter flow only. Griffiths z8 supported his claim for separation of SCBF into white and grey matter flow primarily on the evidence supplied by Espagno and Lazorthes 17,18 who injected microliter quantities of l~3Xenon into cerebral cortical grey matter and subcortical white matter and monitored the decay curves. Fast and slow monoexponential decay curves were observed after injection into grey and white matter, respectively. Similar results have been reported after local injections of SSKrypton into cerebral grey and white matter in dogs4L Griffiths 2s attempted to identify the site of injection with Congo Red dye in some of the animals and found that the dye was confined to the dorsolateral white matter in some dogs, but in others the dye was in the dorsal grey matter and in a small rim of surrounding white matter. In the former animals, monoexponential clearance curves were obtained and in the latter biexponential curves. Mean white matter flow was 15.7 ml/100 g/min and mean grey matter flow was 48.4 ml/100 g/min, although there was considerable variability in the flow values for grey matter which ranged from 26.7 to 86.0. These mean values are quite similar to those recorded by Landau et al. 47 and Sandier and Tator 56 using the autoradiographic technique. Although Griffiths 28 may have succeeded in differentiating grey and white matter flow, he based his subsequent studies 29,3° on white matter flow only due to the difficulty experienced in obtaining reproducible values for grey matter flow in the same dog. The fact that only white matter flow gave reliable results underlines the inadequacy of the 133Xenon intramedullary injection technique to provide detailed information about SCBF in a truly regional manner. Thus the direct injection of l~aXenon into the spinal cord to measure SCBF has serious limitations. The insertion of a needle into the cord must cause some degree of tissue damage, however minimal. Flow can only be measured in the area immediately around the site of injection and not in the whole cross-sectional area of the cord each time. The major limitation is that the site of injection of xa3Xenon cannot be precisely

187 defined, and therefore, the region in which flow is measured cannot be precisely defined. For example, flow in grey and white matter cannot be accurately differentiated. In 1973 Ducker and Garrison v used the clearance of the inert gas argon to measure SCBF. A mixture of 20 ~o argon, 20 ~o oxygen and 60 ~ nitrogen was given via an endotracheal tube to primates, and the argon concentration in the spinal cord was measured with a vacuum mass spectrometer probe inserted into the cord at the thoracolumbar junction. The gas mixture was stopped once the tissues were saturated and the clearance of argon from the cord monitored with the probe. SCBF was found to range from 11 to 19 ml/100 g/min, with the majority of animals having values between 14 and 15 ml/100 g/min. The advantages of this technique, like the 138Xenon method, is that measurements may be repeated over a period of time to investigate the effect of various agents on SCBF. In addition, tissue pO2 and pCO2 can be measured at the same time as blood flow using the mass spectrometer. However, this technique can only measure flow in one small area of the cord at a time, and the actual site of measurement is difficult to control. The values they obtained suggest that the probe was only measuring white matter flow. The most important disadvantage is the size of the mass spectrometer probe which is 1 mm in diameter, nearly one-fifth of the diameter of a mature rhesus monkey spinal cord in the thoracolumbar region. This must cause considerable damage when it is inserted into the cord and would preclude its use for accurate flow measurement. A variation of the inert gas clearance technique, the hydrogen clearance technique, was used in 1974 by Kobrine et a145,46 to measure primate SCBF. Platinum electrodes, 250/~m in diameter, were placed in the lateral white columns and in the 'central' cord. Hydrogen gas was added to the inspired air and the subsequent changes in potential continuously monitored by the electrodes as the hydrogen was removed from the tissue by the blood. The washout curves were then used to measure tissue blood flow in a similar fashion to other gas desaturation techniques. They claimed to be able to measure SCBF in small volumes of tissue, less than 0.5 cu.mm. At the Tv-TII level, mean white matter flow was 17.5 ml/100 g/min while flow in the 'centre' of the cord (presumably mostly grey matter) was only 14 ml/100 g/min. The finding of similar values for white and grey matter flow may be explained by the very rapid diffusion of hydrogen through tissues. Thus a probe in the central grey matter of the cord would be measuring hydrogen washout in the grey and a large part of the surrounding white matter and the fast component of the washout curve, reflecting rapid grey matter flow, would be obscured by the prolonged slow component reflecting the lower white matter flow. This places a severe restriction on the hydrogen clearance technique when it is desired to achieve resolution of flow in very small areas as is required in SCBF. Like the previous inert gas clearance method, this technique traumatizes the cord with the electrodes and cannot differentiate grey and white matter flow. Griffiths et al. 32 have also recently used the hydrogen clearance technique to measure SCBF in dogs and baboons. White matter flow in dogs was 11.5 and in baboons 13.7 ml/100 g/min while grey matter flow was 10.8 and 16.5 ml/100 g/min in the 2 species, respectively. These data further demonstrated the unsuitability of hydrogen clearance for measuring grey and white matter flow in the spinal cord.

188 Indicator fractionation techniques have been used by Flohr et al. 2a-25 and Bingham et al. 1 Flohr et al. 23-25 used 131I labeled macro-aggregated albumin particles as the tracer. The albumin particles were injected directly into the left ventricle of cats and 4 min after injection the animals were sacrificed and the spinal cord removed. Cardiac output was determined prior to the tracer injection, and SCBF was then calculated using the values for the cardiac output, the local tracer concentration and the total amount of tracer injected. The local tracer concentration was determined in segments of the whole cross-section of the cord so that the values obtained provide composite data for SCBF in that entire segment, rather than regional SCBF, at a particular time. Differentiation between grey and white matter flow was not made, although this would have been possible with this technique if discrete areas of the cross-sections had been sampled. Whole segment flow (grey and white matter flow) for the cervical, thoracic and lumbar areas were found to be 20.3, 16.5 and 23.7 ml/ 100 g/min, respectively. Bingham et al. 1 substituted [14C]antipyrine as the tracer and using a modification of Sapirstein's indicator fractionation technique ss measured SCBF in primates. White matter and grey matter SCBF were differentiated by dissecting the grey matter away from the surrounding white matter. White matter SCBF varied from 13.9 ml/100 g/min in the midthoracic region to 19.7 and 2t.7 ml/100 g/ min in the cervical and lumbar regions, respectively. Grey matter SCBF was 48.4, 40.6 and 43.7 ml/100 g/min in the cervical, midthoracic and lumbar regions, respectively. This appears to be a satisfactory technique, but has the disadvantage of requiring microdissection of white matter from grey matter with the possibility of contamination. In addition, the animal must be sacrificed. Although the few quantitative studies on SCBF show considerable variation in their values it can be seen that in general grey matter flow appears to be approximately' 50-70 ml/100 g/rain and white matter flow approximately 10-15 ml/100 g/min, indicating a flow ratio of about 5-I between grey and white matter which is similar to the grey-white flow ratio for the brain. Cerebral grey and white matter blood flow values have also varied considerably depending on the species, site of measurement and method employed but on the average the values for cerebral grey and white matter flow are somewhat higher than those described for the spinal cord grey and white matter. For example Revich et al. ~5 using the [14C]antipyrine autoradiographic technique in cats found cortical grey matter flow to be 109 ml/100 g/min whereas subcortical white matter was 21 ml/100 g/rain. Similarly Eklbf et al. 16 measured regional cerebral blood flow in the cortex of rats using 4 indicators, [14C]antipyrine, [14C]ethanol, [all]water and t33Xenon, and found cortical grey flow values between 95 and 125 ml/100 g/min. In squirrel monkeys Blair and Waltz 2 have recorded mean values of 118 ml/100 g/min for grey matter flow and 49 ml/100 g/min for white matter flow using the [14C]antipyrine autoradiographic technique. An evaluation of the above quantitative methods used to measure SCBF detects flaws in all. However, the indicator fractionation technique and the autoradiographic technique appear to offer the greatest advantages. In particular the high resolution of autoradiography in contrast to microdissection makes it the method of choice for the measurement of regional SCBF. This methodology does not require any injections

189 or insertions of probes into the cord, and thus completely eliminates local cord trauma at the site of measurement. Its major shortcoming is that the animal must be sacrificed at the time of flow measurement necessitating the use of groups of animals at varying time intervals for the study of sequential changes. In contrast, the 13aXenon washout technique, the argon washout method and the hydrogen clearance technique are all invasive techniques requiring the insertion of needles or probes directly into the cord which must cause some degree of cord injury at the site of measurement. In addition, none of these methods can resolve grey and white matter flow with any degree of certainty, as indicated by the divergent results which were obtained when this was attempted. For example, Griffiths2s found grey matter flow with 13aXenon washout to be 48.4 ml/100 g/min, whereas Kobrine et al. 45,46 and Griffiths et al. 82 found grey matter flow to be between 10.8 and 16.5 ml/100 g/min with the hydrogen clearance technique. These 3 methods, however, do provide the opportunity to perform sequential studies on each animal. The particle distribution method of Flohr 2a-25 also has major limitations since it only measures whole cord segment blood flow and does not provide detailed information of grey and white matter flow. Such information is considered to be essential for an understanding of normal SCBF and its changes in pathological states. It is pertinent to note here that the utilization of quantitative autoradiography of chemically inert, radioactive, diffusible tracers has not only made it possible to measure blood flow in the central nervous system but has led to the development by Sokoloff and co-workers as of the [14C]deoxyglucose method for the quantitative determination of local cerebral glucose utilization. This technique has already provided valuable data as to local glucose consumption within various functional and structural components of the brain and no doubt will soon be applied to the measurement of regional metabolism in the spinal cord.

( B) Non-quantitative studies Several non-quantitative methods of studying SCBF have been used, and although they have not been as informative as the quantitative methods they have provided some information on changes in flow due to various physiological, pharmacological and pathological factors. The most commonly used has been the heat clearance method with thermoelectric devices which have been either embedded in the cord 22 or placed on the cord surfaces,9,41,42,50-53,66,67. Changes in blood flow produce changes in the temperature of the thermocouple junctions which in turn lead to variations in electrical current which can be measured. Although they provide continuous monitoring of flow, heat clearance techniques can only show a relative increase or decrease in SCBF. The method has additional shortcomings. For example, thermocouples embedded in the cord cause damage and those placed on the surface of the cord record flow in superficial levels only. Like the other techniques involving probes or needles, the heat clearance technique only depicts flow in a small segment of the cord. Other qualitative methods include the intravenous injection of fluorescent indicators such as fluorescin65 or thioflavine S to outline the spinal cord vasculature8-6.

190 TABLE II

Advantages and disadvantages of methods of measuring spinal cord blood flow 1. Quantitative techniques A. Radioactive isotope clearance - - la3Xenon. 1. Advantages: measurements can be repeated in the same animal. 2. Disadvantages: requires needle insertion into the cord causing trauma; difficult to differentiate grey and white matter flow; only measures flow in one small area of cord at a time. B. Inert gas clearance - - Argon. 1. Advantages: measurements can be repeated in the same animal. 2. Disadvantages: large mass spectrometer probe inserted into cord causes trauma; cannot differentiate grey and white matter flow; only measures flow in one small area of cord at a time. C. Inert gas clearance - - hydrogen. 1. Advantages: measurements can be repeated in the same animal. 2. Disadvantages: electrode insertion into cord causes trauma; measures flow in a large tissue volume; cannot differentiate grey and white matter flow. D. Particle distribution method - - 18~I macro-aggregated albumin. 1. Advantages: no trauma to the cord involved. 2. Disadvantages: only measures flow for a whole cord segment and thus cannot differentiate grey and white matter flow; only measures flow at one particular time. E. Indicator fractionation technique - - [~4C]antipyrine. 1. Advantages: no trauma to cord. With microdissection can differentiate total white matter and grey matter SCBF. 2. Disadvantages: only measures flow at one particular time. Lower resolution than G. F. Inert tracer uptake - - tri-fluoro-iodomethane (CFz13q). Advantages: clearly differentiates white and grey matter flow; very high resolution of flow within grey and white matter; no trauma to cord involved. 2. Disadvantages: only measures flow at one particular time, and requires groups of animals at different times to study sequential changes; technically difficult. G. Inert tracer uptake - - [~4C]antipyrine. 1. Advantages: same as for E. With scanning microscope photometer provides resolution to 0.1 sq. ram. 2. Disadvantages: same as for E, except technically easier.

2. Non-quantitative techniques A. Heat clearance method. 1. Advantages: continuous monitoring of flow; only atraumatic technique available for human SCBF (surface probe).

2. Disadvantages: Non-quantitative, only records flow changes; requires probe insertion into the cord to measure intramedullary flow causing trauma. B. Vascular outline methods - - fluorescent and microradiographic. 1. Advantages: depicts patent vessels in vivo. 2. Disadvantages: l~on-quantitative; does not measure flow per se.

Similarly, m i c r o r a d i o g r a p h i c studies o f c o r d vessels filled with a colloidal b a r i u m suspension have been used to study the vasculature o f the spinal c o r d including the extrinsic vessels, vessel density, and ' w a t e r s h e d ' areas ~7,a4,~,68. These studies in c o n j u n c t i o n with earlier w o r k 20,85,al using v ar i o u s m e t h o d s to outline the spinal c o r d vasculature have clearly s h o w n that vessel density, particularly capillary density, is m u c h higher in grey m a t t e r t h a n in white matter. T h e y have also s h o w n t h a t capillary density is relatively u n i f o r m t h r o u g h o u t the white matter, whereas in grey m a t t e r it is m a r k e d l y different in v a r i o u s parts o f the grey m a t t e r being densest in areas c o n t a i n i n g m a n y cell bodies such as the a n t e r i o r grey h o r n ~0. T h e advantages a n d d i sad v an t ag es

191 of the quantitative and non-quantitative techniques used to measure SCBF are listed in Table II.

( C) Physiologicalfactors affecting normal spinal cord bloodflow A few studies have been performed to examine the effect on SCBF of varying physiological parameters such as PaCO2, PaO2 and blood pressure.

(a) PaC02 The arterial pCO~ has been shown to be the most important physiological parameter affecting SCBF. Flohr et al. 2a,25 using the particle distribution method in anesthetized cats found that blood flow in whole segments of the spinal cord was linearly related to PaCO2 although the absolute sensitivity of the lumbar, thoracic and cervical cord segments to PaCO2 was different (the absolute sensitivity of SCBF to PaCO2 being defined as the change in SCBF divided by the change in PaCO2). The values found were 1.17, 0.91 and 0.54 ml/100 g/min/torr for lumbosacral, cervical and thoracic cord, respectively. The effect of PaCO2 changes have also been studied by Smith et al. 6°, Ducker and Perot 12, and Griffiths29 using the laaXenon clearance technique. Smith et al. s0 in their experiments on the goat thoracolumbar cord found that the mean SCBF decreased from 17.4 ml/100 g/min when the PaCO2 was 39.3 torr to 8.5 ml/100 g/min when the PaCOz was reduced to 16.8 torr. In contrast, elevation of the PaCO2 from 37.4 to 59.4 torr increased mean SCBF from 13.0 to 19.6 ml/100 g/min. However, they also found that in 6 goat studies, the CO2 response of SCBF fell into 2 groups of high and low absolute sensitivity. The high sensitivity group had a mean change of 0.617 ml/100 g/min/torr while the value for the low sensitivity group was only 0.154 ml/100 g/min/torr. The authors were unable to explain the dichotomy in the PaCO2 sensitivity observed. Ducker and Perot 12 in their experiments in the canine thoracolumbar cord found that elevation of the PaCO2 'over 50' torr increased mean SCBF from 15.2 ml/100 g/min to 19.4 ml/100 g/min, and reduction of the PaCO2 to 'below 30' torr produced a fall in mean SCBF to ll.1 ml/100 g/min. Griffiths2a,al also studied the effect of PaCO2 on the canine thoracolumbar white matter. PaCO2 was varied between 20 and 140 torr and a linear relationship was found between SCBF and PaCO2 with the absolute sensitivity to PaCO2 being 0.36 with ~aaXenon clearance and 0.48 ml/100 g/min/torr with hydrogen clearance. In these studies only white matter blood flow was recorded. Kobrine et al. 4a,44 used the hydrogen clearance technique to demonstrate a linear increase in SCBF from 50 to 110 torr PaCO2 in the white matter of the primate cord in the midthoracic region. However, in contrast to Griffiths29,al, Smith et al. 6° and Ducker and Perot 12 they found that between I0 and 50 torr, SCBF remained constant at 17 ml/100 g/min. These results are summarized in Table III. The majority of the evidence indicates that a linear relationship exists between the PaCO2 and SCBF although some disagreement exists at lower values of PaCO2. The differences found in the sensitivity of SCBF to PaCO2 among the various studies may reflect the problems involved in the methodology as discussed above. In addition, due to the methodology employed, the relationship between the grey matter flow and PaCO2 could not be recorded.

192 TABLE III Sensitivity of normal SCBF to PaC02 Method

Author and Ref.

I. laaXenon washout

(a) Smith et al. 6°

2. Hydrogen clearance

Goats thoraco-lumbar, white and grey matter (b) Ducker and Perot 12 Dogs thoraco-lumbar, white and grey matter (c) Griffiths29 Dogs thoraco-lumbar, white matter only (a) Kobrine et al. 43,44

(b) Griffithsal

3. Particle distribution

Species and cord segment

Flohr et al. 2~,2~

Rhesus monkeys thoracic, white matter only Dogs lumbar, white matter only Cats cervical, thoracic, lumbo-sacral, white and grey matter at all levels

ASCBF/PaCOz roll 100 g/min/torr

(i) 0.617 (ii) 0.154 approx. 0.4 0.36

linear increase in SCBF from 50-100 torr 0.48

0.91 0.54 1.17

Several qualitative studies on the effect of PaCO2 on SCBF have also been performed in experimental animals, and in the main support the quantitative evidenceS, 22,5°-52. Palleske and Hermann 52 working with dwarf pigs and the heat clearance surface probe showed a relative increase in SCBF in the lumbar cord when 5-8 % COz was added to the inspired gas mixture. It is interesting to note that Wullenweber 67 has used the same technique as PaUeske and Hermann 52 in patients undergoing spinal cord surgery. During CO~ accumulation caused by apnoea or rebreathing, an increase in SCBF was found, and during hyperventilation, a decrease. Surface cord flow has also been studied with a Peltier flow device, placed on the dorsal cord of rhesus monkeys at the cervical-thoracic junction to measure surface temperature changes in the cord s,41,42. A prompt sustained increase in SCBF was noted when 10% CO2 was added to the respiratory gases. In the study by Kindt et al. al,a2 with the heat clearance method cervical cord transection did not alter the response indicating a local mechanism of PaCOg action. (b) P a 0 2 Less information is available on the effect of the PaO2 on SCBF. Flohr et al. 2~ in their cat experiments described above found no change in SCBF when the PaO~ was varied from 55 to 160 torr with the PaCOz and blood pressure maintained in the

193 normal ranges. Only under hypercarbic conditions did the SCBF respond to PaO2 change. With increased PaCO2 SCBF increased steeply as the PaO~ fell below 70 torr. Griffiths29 measured flow in the white matter of the dog thoracic cord as previously described and confirmed that SCBF did not alter with decreasing PaO2 until the PaO2 reached about 60 torr. Below 60 torr, SCBF increased sharply reaching maximal levels at PaOz of 30--40 torr. A feature also noted by Griffith29 was that below a PaO~ of approximately 30 torr (blood oxygen saturation of about 60 %) SCBF decreased. Thus from these two reports it seems that there is a threshold for PaO2 at approximately 60 torr below which SCBF increases, and that increases in PaO2 above the threshold do not affect SCBF. Flohr et al.'s z5 results indicate that this threshold is elevated under hypercarbic conditions. The reason for Griffiths29 observation that SCBF decreased with very low PaO2 levels is not known at present. SCBF has also been shown to increase in hypoxia by Palleske and Hermann 5z using the heat clearance probe technique when they ventilated dwarf pigs with 98 % NzO and 2 % O3 for 3-5 min. It is noteworthy that SCBF increased even though blood pressure fell during the period of hypoxia.

(c) Blood pressure. The effect of variations of blood pressure on SCBF have also been investigated by Ducker and Perot TM, Griffiths80 and Kobrine 4s,aa using the 138Xenon clearance and hydrogen clearance techniques. Ducker and Perot TM reported that SCBF did not change with systemic blood pressure alteration, and Griffithsz° demonstrated no significant variation in white matter flow in the blood pressure range of 60-150 mm Hg. However, below 60 mm Hg, flow decreased with reduction in pressure. Kobrine et al. az,4a also showed that SCBF in the white matter did not vary significantly for a mean arterial blood pressure range of 45-135 mm Hg. Below 45 mm Hg SCBF decreased linearly and above 135 mm Hg SCBF increased linearly. Similar results were observed if high cervical cord section was performed indicating a local regulatory mechanism. Similarly Flohr et al. z5 demonstrated with the particle distribution method that there was no change in SCBF when the mean arterial pressure varied between 60 and 160 mm Hg. This phenomenon that the blood pressure may be altered between 60 and approximately 150 mm Hg without causing a persistent or significant change in SCBF under normocarbic and normoxic conditions is known as autoregulation and has also been demonstrated for the cerebral circulation38,4s,54. It is of interest to note the effect on SCBF of simultaneously varying blood gas tensions and blood pressure. Gritfithsz0 found that under conditions of combined hypoxia and normocarbia, or combined normoxia and hypercarbia, SCBF fell progressively with a decrease in blood pressure. Flohr et al. 25 also noted that in hypercarbic states SCBF increased with blood pressure increase. However this variation in SCBF with blood pressure did not occur in hypercarbic animals. Qualitative observations of the effect of blood pressure variations on SCBF in animals and man have been made2~,41,a2,50,66 with heat clearance devices. In all cases it was noted that although SCBF showed an initial increase when blood pressure was elevated, SCBF soon returned to normal levels even though the blood pressure re-

194 mained high. This initial increase in SCBF associated with blood pressure elevation was not seen in the studies using quantitative techniques because measurements were made only under steady state conditions. Thus it has been shown that normal cord blood flow is highly sensitive to changes in PaCO2, less sensitive to PaOz variation and exhibits autoregulation in response to arterial blood pressure changes.

(D) Pharmacologicalagents affecting spinal cord bloodflow Very few investigations have been performed to evaluate the effects of pharmacological agents on SCBF. With heat clearance techniques, Field et al. 22 showed that intravenous administration of sodium pentobarbitone or o-tubocurarine caused a decrease in SCBF. Palleske ~° investigated several agents of which only a few showed effects on SCBF as indicated by heat clearance techniques. Euphyllin (theophyllinethylenediamine) given intravenously produced a decrease in SCBF, whereas papaverine or Eupaverin (benzylethyldimethoxyisochenoliniumchloride) given intravenously caused an increase in SCBF. Using the quantitative autoradiographic technique, Freygang and Sokoloff~6 showed that light thiopental anesthesia had no significant effect on either grey or white matter flow in the feline spinal cord. Similarly Griffithsz8 found no significant difference in SCBF in white matter in dogs anesthetized with either trichloroethylene or Halothane or pentobarbitone using 133Xenon clearance to measure flow. Griffiths' findings with pentobarbitone conflict with those of Field et al. 22. CONCLUSION A critical analysis of the methodology currently available to measure SCBF indicates that the best method for most situations is autoradiography using [14C]antipyrine. This quantitative method offers several advantages: extremely high resolution leading to clear differentiation of white and grey matter blood flow; measurement of SCBF in the whole cord at any one time; avoidance of trauma to the cord at the time of measurement; provision of a pictorial display of SCBF in histological sections of the entire cord. It is particularly useful in the study of the effect of experimental trauma on SCBF because the corresponding tissue section is available for histological study allowing correlation between histopathology and altered SCBFSL Although the [14C]antipyrine autoradiographic technique has not been used to date to determine the effects of varying physiological parameters on grey and white SCBF, it is clear that PaCO~ is an important factor in determining SCBF. Hypercarbia leads to increased SCBF whereas hypocarbia decreases SCBF. Hypoxia also increases SCBF. In addition SCBF exhibits autoregulation in response to changes in arterial blood pressure. The available data on the effects of drugs on SCBF is minimal, The use of the [14C]antipyrine autoradiographic technique would lead to an increase in knowledge in this field.

195 ACKNOWLEDGEMENTS A. N. Sandier was a Research Fellow of the Medical Research C o u n c i l o f Canada. The w o r k was supported by Medical Research C o u n c i l G r a n t MT-4064. G r a t e f u l a c k n o w l e d g e m e n t is made to Mrs. L. M a r m a s h , Miss V. E d m o n d s , R. N. a n d Mrs. M. L a m for technical assistance.

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