cortical in hypotension - bmj

Journal of Neurology, Neurosurgery, and Psychiatry, 1973, 36, 906-913

Cortical blood flow in controlled hypotensionas measured by thermal diffusion'

L. PHILIP CARTER AND JAMES R. ATKINSON2

From the Neurosurgical Research Laboratory, Barrow Neurological Instituteof St. Joseph's Hospital and Medical Center, Phoenix, Arizona, U.S.A.

SUMMARY A thermal diffusion flow probe which gave a continuous, dynamic, quantitative recordof cortical blood flow (CBF) was used to assess CBF in experimental animals with controlled hypo-tension. Acute hypotension was produced by trimethaphan camsylate, halothane, and sodiumnitroprusside. Halothane produced less reduction in CBF per drop in blood pressure than the othertwo agents.

Controlled hypotension has been a valuableoperative adjunct for the neurosurgeon since1946 when Gardner first used arteriotomy tofacilitate removal of a large olfactory groovemeningioma. In 1953 Wiklund recommendedpharmacologically controlled hypotension foraneurysms, vascular tumours, arteriovenousmalformations, and increased intracranialpressure with cerebral oedema. As experiencewith the technique accumulated, the primaryindication has become the direct approach tointracranial aneurysms. Three modes of hypo-tension are currently used: trimethaphancamsylate (Arfonad), deep halothane anaesthesia,and sodium nitroprusside. This study wasdesigned to evaluate the effects of these threeagents on cortical blood flow (CBF) because ofthe ever-present spectre of cerebral ischaemiawith controlled hypotension.

Cerebral blood flow may be measured bynumerous methods including Kety-Schmidt's(1945) nitrous oxide diffusion washout, electro-magnetic flowmeters on large vessels, venousoutflow collection, radioactive gas diffusionwashout (Lassen and Ingvar, 1961), and auto-radiography (Landau, Freygang, Roland,Sokoloff, and Kety 1955). Since a dynamiccontinuous record of tissue perfusion was

I Resident Award Paper, Western Neurosurgical Society, presented atColorado Springs, 2 November 1971.2 Reprint requests: Dr. James R. Atkinson, Division of Neurosurgery,Barrow Neurological Institute, 350 West Thomas Road, Phoenix,Arizona, 85013, U.S.A.

desired, a thermal diffusion probe as describedby Brawley (1968) was investigated.Gibbs first measured blood flow with a thermal

diffusion device in 1933, and in more recentyears Grayson (1952) was able to show a linearrelationship between blood flow and the heatconductivity increment in tissue. Betz andWiillenweber (1962), Betz, Ingvar, Lassen, andSchmahl (1966), Betz and Heuser (1967), Betz(1968), using a technique described by Hensel(1959), have made extensive measurements ofcerebral cortical blood flow. Their probe had twosmall gold plates, one heated and one neutral,which were placed on the cortex. Temperaturedifference between the two plates was found tobe related to CBF to a depth of 15 mm. Betzet al. (1966) pointed out that their results wereaffected by local vascular geometry, whichmight account for their lack of correlation ofCBF as measured by 85Kr clearance and thermaldiffusion between animals of the same species.Brawley (1968) used a Peltier stack to create aprobe with one heated and one cooled plate.This probe utilized the Peltier thermoelectriceffect to produce a thermal gradient by currentflow through a semiconductor. The temperaturegradient was conducted to the tissue by twometal plates which were thermally contiguouswith the respective hot and cold sides of thesemiconductor stack3, but electrically isolated3 Model 837, Borg-Warner Thermoelectrics, Wolt and AlgonquinRoads, Des Plains, Illinois, 60018, U.S.A.

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Cortical bloodflow in controlled hypotension as measured by thermal diffusion

CONTACT SURFACE

Steel Connecting Rod

Output From Thermocouples

Peltier Stack

T0.5 cm.

Gold Contact Plates

'CortexPower InPut to Stack

FIG. 1. Schematic drawing offlow probe. 'L"shapedgoldplates are soldered to the stack and rest on the cortex.300 mA ofdirect current activates the stack, and the temperature difference is recordedfrom the thermocouples.

from its current. The difference in temperaturebetween the two plates varied with CBF. Ideallyambient temperature variations would not affectthe recorded temperature differences.

METHODS

Our probe is a modification of Brawley's (Fig. 1). An'L'-shaped gold plate was soldered to each surfaceof the Peltier device and copper-constantine thermo-couples were spot welded to the approximate centreof the back of the cerebral contact surface and wereconnected with opposite polarity so that the outputof the pair was zero when at the same temperature.Temperature differences of the thermocouplesproduced an output of the order of hundreds ofmicrovolts which was recorded on a Grass model 7polygraph. A small steel rod was used for fixation ofthe probe to the head holder, and the probe, with theexception of the cerebral contact surfaces, wasencased in epoxy resin.The contact plates each measured 0 50 cm x

0 75 cm. Three hundred mA direct current throughthe Peltier stack produced the temperature gradientat the plates of 50 C above and 30 C below thecortical temperature. The temperature differencesvaried with cortical blood flow. In vitro tests of theprobe revealed that, despite a gradual drop in surfacetemperature from 35.25° to 26.000 C, no significantchanges in temperature gradient between the twoplates occurred, thus demonstrating its independence

of cortical ambient temperature. The time constantof the probe was found to be 4-2 sec.

Twelve mongrel cats anaesthetized with intra-peritoneal pentobarbitone (35 mg/kg), except onewhich was induced and maintained on inhaledhalothane alone, had Teflon cannulae inserted intoboth femoral artery and femoral vein and tra-cheostomy performed. The arterial cannula wasconnected to a Statham strain gauge for recordingblood pressure, and the venous cannula was used forinjection of drugs. Additional intravenous pento-barbitone was used to keep the animal well sedatedthroughout surgery, and a small left craniectomywas performed. Great care was taken to obtain goodhaemostasis before the dura mater was opened.Fifty millilitres D5W and 7 to 9 mEq NaHCO3were given intravenously during the surgery tocorrect any slight ketosis that may have been presentbecause the cats were fasting the night before surgery.The animals were then placed on a positive pressurerespirator breathing room air with supplemental02 and paralysed with gallamine triethiodide(5 mg/kg). After at least 30 minutes for stabilization,arterial blood gases were drawn and, if necessary,adjustments in volume and rate of respiration weremade followed by repeat estimation of blood gases.Blood pressure (BP) and respirations were monitoredby strain gauges. To record, the probe was loweredonto the crown of a gyrus, attempting to avoid largesurface vessels. Enough pressure was applied to holdcontact with the cortex without causing any signifi-

LATERAL

Output FromThermocouples

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L. Philip Carter and James R. Atkinson

B P 150 -, r, N r .Imm Hg

C_CBFcc

100 gm-min

75-

0

35

0-

5 SecEvent I

FIG. 2. Intravenous KCI was given at the mnarker on the lower tracing. A sudden drop in BP (mm7Hg) and CBF(ml./100 g/mini) was noted. When CBF reached a steady state the thermocouple voltage was recorded as the 'noflow' or 'dead brainl' value. Lower tracing is time with upward deflections at five second intervals.

cant deformity. The plates and surrounding cortexwere covered. Connecting the two contact platestogether electrically revealed no significant changes ingradient as measured by the thermocouples, indicat-ing the absence of a significant bioelectric potentialbetween the two plates. To evaluate the approximatesensitivity of the probe, layers of moist cottonoidswere placed between the probe and cortex. Changesin blood flow could be detected readily through3 mm of cottonoid but were markedly attenuated.

Calibration of the Peltier flow probe was carriedout by correlation with 133Xe diffusion-washoutcurves in the cat. In four of the animals large rightcraniectomies were performed. After the dura materwas opened, the cortex was covered with polyvinylchloride film. A 125 in. thin mica end windowGeiger-Muller tube with output fed to a ratemeterand then to the polygraph was placed as near theright cortex as possible. One microcurie of 133Xedissolved in 0-1 ml. saline followed by a 0-3 ml. flushof saline at 37° C was injected rapidly into thebrachiocephalic artery through a Teflon catheter inthe right subclavian artery. The blood flow probe onthe left hemisphere was monitored while obtaining133Xe diffusion-washout curves on another channelin order to ensure uniformity of CBF.

It was felt that the washout curves from the

exposed cortex of the cat would give the mostaccurate assessment of CBF, since it is extremelydifficult to separate the extracranial from the cerebralcirculation in this animal. Harper and Jennett (1968)have shown that the beta curve, presumably strictlycortical flow, and the fast component of the gammacurve correlate quite well. Only the fast componentwas considered, since we were concerned only withcortical flow. The CBF was altered by changing thePco2, as well as a slow phenylephrine intravenousdrip which increased CBF and blood pressure. Allcurves with a peak of less than 9,000 counts perminute and in which the Peltier flow channel did notshow a constant flow throughout the diffusion curvewere discarded.The half time (t 1/2) in minutes for 133Xe diffusion

from grey matter was found, and, using principlesadvocated by Lassen and Ingvar (1961) with H0edt-Rasmussen's (1967) correction for Hb, the CBF inml./100 g/min was calculated.

CBF in ml./100 g/min = 10lO 2693 A

A is the brain blood partition coefficient for 133Xe.A dead brain thermal value for the flow probe was

found at the end of the experiment after cardiacarrest caused by intravenous injection of KCI

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(Fig. 2). The probe output voltage for each 133Xedetermination was found and subtracted from thedead brain value. Fourteen values of CBF asdetermined by the flow probe and 133Xe washoutcurves were obtained.

In the second phase of the experiment threemethods of producing hypotension acutely wereutilized: (1) trimethaphan camsylate (Arfonad)10 mg/100 ml. D5W intravenous drip, (2) deephalothane anaesthesia which was controlled by ahalothane analyser-vaporizer-controller4, and (3)sodium nitroprusside 2 mg/100 ml. D5W intravenousdrip. Halothane concentrations were varied from 1to 4%°. Two percent halothane was found to producerapid hypotension. Blood pressure (BP) was loweredin 1 5 to 10 minutes using several different agents inthe same cat as well as the repeated use of the same

4 Courtesy of Ohio Medical Products.

225-,

200-

175-

*- 150-D

125.05

100-

'u 75-

50

25-

/x /

x/ /

/ // /

/ /

/X/

/ /

Probe in cc/lOOgm. - min. = 2.18 (Xe 133) - 8.58

RMS Error = 11.71 pv

I I I I I0 25 50 75 l00 1253Xe ml/lOOg tissue-min.

FIG. 3. X represents actual data points. The solidline is the least squares plot of these points, and thebroken line represents root mean squared (RMS)error.

agent in the same cat. The results of normalized CBFchanges per drop in BP were correlated with theDigital PDP-12 computer.

RESULTS

A linear relationship was noted between CBF asmeasured by 133Xe diffusion washout and theflow probe. When plotted in a least squaresmanner on the Digital PDP-12 computer therelationship was found to be:CBF probe in ml./100 g/min =

2-18 CBF 133Xe-8-58Root mean squared (RMS) error = 11-7 ,v(see Fig. 3)Data reduction in the pharmacologically

controlled hypotension experiments began withthe elimination of all data from animals whichhad suffered haemorrhage, cortical contusion,hypercarbia, or hypoxia, since damage to thecerebrovascular regulatory system may haveoccurred. This same regulatory system would belost outside the autoregulatory range of BP,therefore any data with a minimum mean BPbelow 70 mmHg were discarded. CBF auto-regulation has been demonstrated by Haggendaland Johansson (1966) to occur under normo- andhypocapnic conditions in ranges of pH from7-26 to 7-87. Final constraints for control valueswere then defined as Pc02 from 24-5 to 40-5mmHg, pH from 7-26 to 7-45 and CBF above24 ml./100 g/min. Twenty five observations ineight animals met the above criteria.

Control CBF was below normal values forawake animals but in an acceptable range foranimals under barbiturate anaesthesia and wasan average of 48-1, 61-9, and 56-1 ml./100 g/minfor the trimethaphan camsylate, sodium nitro-prusside, and halothane groups respectively.The one animal that did not receive a barbituratemaintained a higher CBF than the otheranimals.

Because of the difference in techniques ofadministration of the agents, the time to reducethe BP was quite variable. The average time toproduce maximum hypotension in the tri-methaphan camsylate, sodium nitroprusside,and halothane groups was 3-7 min, 3-1 min, and5-2 min respectively. No attempt was made tomaintain hypotension and once hypotensionwas achieved the agent was discontinued and the

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TABLE 1MEAN VALUES FOR THE 25 OBSERVATIONS OF HYPOTENSION PRODUCED BY THREE AGENTS*

Agent Observations Pco2 Control Control iBP° ' CBF% ACBF%(mmHg) BP CBF z1BPz

(mmHg) (ml./100 glniin)

Trimethaphan camsylate 7 33-6 ± 2-4t 1409 ± 3-3 48-1 + 71 32-0 ±25 40-1±7-1 1 227 ± 0229Sodium nitroprusside 9 338 ± 24 142-3 ± 53 61-9±7-6 24-9 2-6 23-6± 44 0-908 ± 0112Halothane 9 31-8±2-4 133-0±3-8 56-1±11-2 22-6±2 5 8-7±2-6 0 365±0-120

* ABP%, and 4CBFY. are the percent changes in BP and CBF.t Standard error of mean.

TABLE 2STATISTICAL EVALUATION OF THE THREE HYPOTENSIVE AGENTS*

Agents Pco2 Control Control A BP° ACBF°1 JCBF%(mmHg) BP CBF zlBP>

Trimethaphan camsylate and nitroprusside NS NS NS NS NS NSTrimethaphan camsylate and halothane NS NS NS Significant Significant Significant

at 05notat*01 at*01 at*01Nitroprusside and halothane NS NS NS NS Significant Significant

at 05notat*01 at*01

* BP was lowered more with trimethaphan camsylate; however, taking this into consideration by using the ratio of ACBFY./zJBP%, halothanehad significantly less effect on CBF.t NS = not significant.

BP was allowed to return to control levels. Ingeneral, the hypotension produced by tri-methaphan camsylate persisted longer thanhypotension produced by the other two agents.CBF autoregulation is best demonstrated by

gradual hypotension (Bozzao, Fieschi, Agnoli,and Nardini, 1968), and, since the rate of changein these experiments is rapid, it is not possible toassess the impact of these agents on the auto-regulation mechanism. We did note that theminimum CBF usually occurred simultaneouslywith maximum hypotension and the CBFgradually returned to normal concomitantly withBP.The three groups were quite comparable,

with no statistical differences regarding controlmean BP, CBF, and PCo2, and met the criteriafor a homogeneous population in an autocontrolexperimental design. The minimum CBF duringcontrolled hypotension was compared withthe control CBF in each individual run regardingpercent change in CBF per percent change inmean BP. Trimethaphan camsylate depressedCBF per drop in BP the most, followed by

sodium nitroprusside, while halothane hadsignificantly less effect on CBF for the samechange in BP (Tables, 1, 2).The CBF as recorded by the flow probe was

linearly related to the cortical flow as determinedby 133Xe diffusion-washout curves. Corticalblood flow decreased with all three hypotensiveagents; however, the percent drop of CBF perpercent drop of BP was significantly less withhalothane than with the other two agents.

DISCUSSION

The linear correlation of thermal diffusionmeasured CBF with radioactive diffusion-wash-out measured CBF was demonstrated up to90 ml./100 g/min and may persist at higher ratesof flow. This correlation is at variance with theresults of Betz et al. (1966, 1967, 1968) whichdemonstrated a reproducible relationship ofCBF as measured by heat clearance and by 85Krwashout in the same animal, with variationsbetween animals. It must be kept in mind thattheir probe differed from the one used in this

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experiment in two important respects: (1) thesize of the cortical contact surface, and (2) thetemperature of the non-heated plate. Both ofthese factors make their probe dependent on thelocal vascular geometry as pointed out by Betzet al. (1966). On the other hand, the probe usedin this experiment has a larger cortical contactsurface area, thus producing an averaging effect,and the non-heated surface is actively cooled,therefore minimizing the thermal effect producedon it by the heated plate.The Peltier flow probe is able to record

continuous changes in CBF in a quantitativemanner with reproducible results from oneexperiment to the next, and acute changes arenoted without difficulty within the limits of thetime constant. The prime disadvantage of theprobe is the need to expose the cortex; however,under the conditions of interest-that is,intracranial surgery-the cortex is exposed.Since the thermal diffusion properties of corticaltissue are relatively constant the probe providesthe means to measure simply regional CBFquantitatively in the surgical theatre as has beendone qualitatively by Betz and Wullenweber(1962).

Other popular methods of measuring CBF allhave some disadvantages when applied to thisparticular experimental problem as well as inthe operating room. The nitrous oxide and radio-active diffusion-washout technique require aconstant blood flow for a period of time and areunable to demonstrate CBF dynamics. Venousoutflow measuring systems usually requireextensive surgery and cannot differentiate arterio-venous shunting from actual tissue perfusion.Examination of pial circulation will give crudequalitative estimates of flow, but, because theflow is proportional to the fourth power of theradius of the vessel, minute changes in the radiuscan alter the flow.The well-known autoregulatory mechanism of

CBF in systemic hypotension has been welldocumented with gradual changes in bloodpressure produced by hemorrhage (Harper 1966).Due to the nature of most CBF measuringsystems very little information is available con-cerning acute pharmacological reduction in BPas occurs in surgically controlled hypotension.

Because of the variations in the character andmodes of administration of these agents it is

BP 150100

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CBF 40-20

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N hItliclol. h.%um/if nlUf/WSJ%uItc infiAsed hc'iwccn11c tlii) (hlt'/lllUItdacf/rIccuionl. of it ICt/(TC/If (X1'kcr.dem1onstratng agUinl U t U/Iocoi tUii/fIt l/ l BP and

rhuiplia taiiic si1aic. (i/Id ITM1 1(1 JlrlOU f/ow ItilCOCCU/TC(i ni/c/h M1/0/ JfmlO//ll/1.

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"' '... ^ I _

CBF 40 -CC 30-0OOgm-minHal 2%

(c) IIypoi...sion p_.od_ccei / 2,,,YU/"liUoiO i,/i-?/i-tiuo/o/. H1lofh/(acl, collcorit/Jt io/1 IA reiMtA)/t/dt o/n M//c

th/i diro i i/ 1P. l..'pitrd deflecfion of tinl/niar cr i.%

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FIG. 4. Three separate tracings demonstratinig theeffect of the three agents in the same animal.

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difficult to compare them. In this experimentalsetting the hypotension produced by halothanewas not as rapid and the hypotension producedby trimethaphan camsylate seemed more per-sistent. Since the speed with which hypotensionis produced may be a factor in preservation ofautoregulation (Bozzao et al., 1968), the moregradual hypotension of halothane may havecontributed to the better preservation of CBFwith this agent.Trimethaphan camsylate acts as a ganglionic

blocking agent and has been used extensively forcontrolled surgical hypotension for many years.Moyer and Morris (1954) demonstrated adecrease in CBF in the awake normotensivepatient with trimethaphan camsylate as well aswith other ganglionic blocking agents. Theyfound a 32% fall in nitrous oxide measured CBFwith a 42% fall in mean BP. During hypotensionthe calculated ACBF%//ABP% is 0762 ascompared with 1 227 for our anaesthetizedparalysed cats. The fall in CBF, while not asgreat as in our experimental animals, wassignificant and did demonstrate that even inawake normal volunteers trimethaphan camsyl-ate will markedly decrease CBF.Sodium nitroprusside has been studied by

Moraca, Bitte, Hale, Wasmuth, and Poutasse(1962) and found to be an excellent agent forcontrolled surgical hypotension because of theprompt appearance and disappearance of itseffects. It is thought to act directly on the vascularmusculature rather than on the nervous control.Very little information is available on its effecton CBF. Waltz (1968) used several agentsincluding sodium nitroprusside to reduce BP incats and found no decrease in CBF innonischaemic cortex. Cortical blood flow wasmeasured with radioactive clearance washoutcurves, and no details of the temporal relation-ship of the agent and recording CBF were given.McDowall (1967) found that halothane

increased CBF in concentrations not sufficientto produce hypotension, and barbiturates areknown to depress CBF (Landau et al., 1955).In a concentration of 2%, halothane rapidlyreduced the mean BP as well as the pulse pressure.In most cases, the flow did not drop as markedlyas with the other agents. Comparison of ananimal that received all three agents is seen inFig. 4. It is obvious that the effect of halothane on

CBF was not as marked as was that of the othertwo.

Using 85Kr and 133Xe Christensen, H0edt-Rasmussen, and Lassen (1965) measured CBFin four patients before and during halothaneanaesthesia. They found a ACBF%0/ABP% of0457 which is comparable with the 0365 ratiofor our animals. In controlled hypotensionhalothane has a less depressant effect on CBFthan sodium nitroprusside and trimethaphancamsylate.

Technical assistance was provided by KennethValikai, B.S.E.E.

REFERENCES

Betz, E., and Wiullenweber, R. (1962). FortlaufendeRegistrierung der lokalen Gehirndurchblutung mitWarmeleitsonden am Menschen. Klinische Wochenischrift,40, 1056-1058.

Betz, E., Ingvar, D. H., Lassen, N. A., and Schmahl, F. W.(1966). Regional blood flow in the cerebral cortex, measuredsimultaneously by heat and inert gas clearance. ActaPhysiologica Scandinavica, 67, 1-9.

Betz, E., and Heuser, D. (1967). Cerebral cortical blood flowduring changes of acid-base equilibrium of the brain.Journal of Applied Physiology, 23, 726-733.

Betz, E. (1968). Measurements of local blood flow by meansof heat clearance. In Blood Flow Through Organs andTissues, pp. 169-176. Edited by W. H. Bain and A. M.Harper. Livingstone: Edinburgh.

Bozzao, L., Fieschi, C., Agnoli, A., and Nardini, M. (1968).Autoregulation of cerebral blood flow studies in the brainof cat. In Blood Flow Through Organs and Tissues, pp. 253-257. Edited by W. H. Bain and A. M. Harper. Livingstone:Edinburgh.

Brawley, B. W. (1968). The pathophysiology of intracerebralsteal following carbon dioxide inhalation, an experimentalstudy. Scandinavian Journal of Clinical and LaboratoryInvestigation, 22, (Suppl. 102), XIII: B.

Christensen, M. S., H0edt-Rasmussen, K., and Lassen, N. A.(1965). The cerebral blood flow during halothane an-aesthesia. Acta Neurologica Scandinavica, 41, Suppl. 14,152-155.

Gardner, W. J. (1946). The control of bleeding duringoperation by induced hypotension. Journal of the AmericanMedical Association, 132, 572-574.

Gibbs, F. A. (1933). A thermoelectric blood flow recorder inthe form of a needle. Proceedings of the Society for Experi-mental Biology and Medicine, 31, 141-146.

Grayson, J. (1952). Internal calorimetry in the determinationof thermal conductivity and blood flow. Journal ofPhysiology, 118, 54-72.

Haggendal, E., and Johansson, B. (1966) Effects of arterialcarbon dioxide tension and oxygen saturation on cerebralblood flow autoregulation in dogs. Acta PhysiologicaScandinavica, 66, suppl. 258, 27-53.

Harper, A. M. (1966). Autoregulation of cerebral bloodflow: influence of the arterial blood pressure on the bloodflow through the cerebral cortex. Journal of Neurology,Neurosurgery, and Psychiatry, 29, 398-403.

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Harper, A. M., and Jennett, W. B. (1968). Simultaneousmeasurement of beta and gamma clearance curves ofradioactive inert gases from the monkey brain. In BloodFlowv Throuigh Organs and Tissues, pp. 214-225. Edited byW. H. Bain, and A. M. Harper. Livingstone: Edinburgh.

Hensel, H. (1959). Messkopf zur Durchblutungregistrierungan Oberflachen. Pflugers Archiv fur die gesamte Physiologydes Menschen iund der Tiere, 268, 604-606.

H0edt-Rasmussen, K. (1967). Regional cerebral blood flow.The intra-arterial injection method. Acta NeuirologicaScandinavica, 43, Suppl. 27.

Kety, S. S., and Schmidt, C. F. (1945). The determination ofcerebral blood flow in man by the use of nitrous oxide inlow concentrations. American Journal of Physiology, 143,53-66.

Landau, W. M., Freygang, W. H. Jr., Roland, L. P., Sokoloff,L., and Kety, S. S. (1955). The local circulation of theliving brain: values in the unanesthetized and anesthetizedcat. Transactions of the American Neutrological Association,80, 125-129.

Lassen, N. A., and Ingvar, D. H. (1961). The blood flow of thecerebral cortex determined by radioactive krypton85.Experientia, 17, 42-43.

McDowall, D. G. (1967). The effects of clinical concentrationsof halothane on the blood flow and oxygen uptake of thecerebral cortex. British Journal ofAnaesthesia, 39, 186-196.

Moraca, P. P., Bitte, E. M., Hale, D. E., Wasmuth, C. E., andPoutasse, E. F. (1962). Clinical evaluation of sodium nitro-prusside as a hypotensive agent. Anesthesiology, 23, 193-199.

Moyer, J. H., and Morris, G. (1954). Cerebral hemodynamicsduring controlled hypotension induced by the continuousinfusion of ganglionic blocking agents (hexamethonium,Pendiomide and Arfonad). Journal of Clinical Investigation,33, 1081-1088.

Waltz, A. G. (1968). Effect of blood pressure on blood flow inischemic and in nonischemic cerebral cortex. The phe-nomena of autoregulation and luxury perfusion. Neurology(Minneap.), 18, 613-621.

Wiklund, P. E. (1953). Controlled hypotension at intracranialoperations. Journal of Neurosurgery, 10, 617-623.

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