Cerebral vascular spasm: A new diagnostic and neurosurgical approach, based on advances in neuropharmacology and neurosciences 9783110847000, 9783110100297

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Cerebral vascular spasm

With compliments

Bayer

Cerebral vascular spasm A new diagnostic and neurosurgical approach, based on advances in neuropharmacology and neurosciences edited by D. Voth and P. Glees in collaboration with E. Betz and K. Schiirmann

W Walter de Gruyter G Berlin • New York 1985 DE

Prof. Dr. med Dieter Voth Klinikum der Johannes Gutenberg-Universität Neurochirurgische Klinik und Poliklinik Langenbeckstr. 1 D - 6 5 0 0 Mainz Prof. Dr. med. Paul Glees University of Cambridge Dept. of Anatomy Downing Street Cambridge CB2 3 D Y Great Britain This book contains 2 0 7 illustrations and 81 tables. For technical German

reasons,

captions

into

it was not always possible

to translate

the

original

English.

CIP-Kurztitelaufnahme der Deutschen Bibliothek Cerebral vascular spasm : a new diagnost. and neurosurg. approach, based on advances in neuropharmacology and neurosciences / ed. by D. Voth and P. Glees. In collab. with E. Betz and K. Schürmann. — Berlin ; New York : de Gruyter, 1985. Dt. Ausg. u. d. T.: Der zerebrale Angiospasmus ISBN 3-11-010029-0 NE: Voth, Dieter [Hrsg.]

© Copyright 1984 by Walter de Gruyter &C Co., Berlin 30. All rights reserved, including those of translation into foreign languages. No part of this book may be reproduced in any form - by photoprint, microfilm, or any other means - nor transmitted nor translated into a machine language without written permission from the publisher. The quotation of registered names, trade names, trade marks, etc. in this copy does not imply, even in the absence of a specific statement that such names are exempt from laws and regulations protecting trade marks, etc. and therefore free for general use. Typesetting and Printing: Buch- und Offsetdruckerei Wagner GmbH, Nördlingen. - Binding: Lüderitz 8c Bauer, Buchgewerbe GmbH, Berlin. - Printed in Germany.

Dedicated in cordiality to Professor Dr. G. Kuschinsky, the critical scientist and engaged academic teacher, on the occasion of his 80th birthday. Mainz, January 1 9 8 4

D. V.

Dagegen werden die Basalarterien zuweilen in anderer Weise zu einem bedeutungsvollen Ausgangspunkt für Meningealhämorrhagien durch das Platzen eines an ihnen befindlichen Aneurysma. Mitunter ist es vorgekommen, daß die Kranken aus einer kurzen Apoplexie wieder zu sich kamen, mehrere Stunden und selbst zwei Tage lang nur über Kopfschmerzen klagten, etwas aufgeregt oder umgekehrt somnolent sind und dann erst von Neuem in das jetzt letale Coma verfallen. H. Nothnagel (Jena) 1878 in: "Handbuch der Krankheiten des Nervensystems" I, S. 170, 174. Doch hat schon Pal (1905) darauf hingewiesen, daß lokale Ischämien durch Arterienkrampf hängig von einer generellen Tonuserhöhung der Blutgefäße vorkommen.

völlig

F. Hiller (München) 1936 in: "Handbuch der Neurologie", O. Bumke/O. Foerster, Band 11, S. 253.

unab-

Preface

Cerebral vascular spasm after subarachnoidal haemorrhage is a serious event for the patient and of grave prognostic consequence. While spasmolysis of some organs largely composed of smooth muscle can be achieved without much difficulty, cerebral angiospasm is far more resistant to treatment. For neurosurgeons the presence of or suspecting cerebral vascular spasm is a contra-indication for operating. Although a postponment of operating on the source of bleeding may hasten the fatal autcome if further bleeding occurs. For these reasons, prevention or treatment of post-haemorrhage spasm which cuts off oxygen and nourishment from reaching vital brain areas, is an urgent problem both for surgeons and for basic vascular research. The main object of the third neuro-science conference at Mainz, was the bringing together of workers in neuroscience, anatomists, physiologists, neuro-pathologists, pharmacologists and clinicians such as neurologists and neurosurgeons closely associated with this problem. W e hope that this combination will advance our knowledge and promote therapeutic advance. W e believe the present volume contains a selection of relevant clinical studies and basic neuro-science studies and reviews closely allied to the urgent clinical problems of angiospasm. At the same time it was important for the neurosurgeons present, to discuss and exchange information when to operate eliminating the arterial aneu-

rysm, to operate early, to wait, how long to wait, what are the chances for recovery and useful survival and whether modern pharmacology — e.g. the calcium blockers — can prevent or alleviate cerebral vascular spasms.

entry

Obvously there were no ready made solutions, but we are certain that the serious discussions and the work in progress communicated here will be beneficial for therapeutic advance and for the benefit of the patient, who can be struck already very early in his lifetime. Mainz-Cambridge, 1 9 8 4

D . V o t h and P. Glees

Contents

I Anatomy of cerebral vessels and regulation of general cerebral blood flow Anatomic variations and anomalies of the cerebral arterial circle of Willis and its central branches (L. Lang) The relation of glia to cerebral blood vessels and neurons (P. Glees) . . . . The innervation of the cerebral nervous system vasculature in the rabbit (A preliminary study) (P. L. Debbage, D. Dwyer, R. Meyermann) Electrical and chemical control of activation processes in vascular smooth muscle (K. Golenhofen) Experimental investigations of noradrenaline- and hydroperoxide induced contractions in segments of carotid arteries (H. Heinle, D. Kling, E. Betz) . Regulating mechanisms of cerebral microcirculation during enhanced and decreased functional activity of nervous tissue (E. Leninger-Follert) . . . . Postischaemic reactivity of pial arteries, an experimental study (C. Haller, W. Kuschinsky) Comparative morphological, biochemical and pharmalogical investigations of a spontaneously active smooth muscle (D. Voth, M. Henn, J. Frisch) . . . . The significance of vascular resistance in reperfusion following cerebral ischaemia (D. Heuser, H. Guggenberger)

3 19 41 49 61 67 75 81 97

II Experimental investigations of the pathophysiology and therapy of cerebral angiospasm Vasospasm in hypertensive rats induced by dihydralazin (Nepresol®) (L. M. Auer, B. B. Johansson, L. Sayama, F. Haydn) Determination of local metabolic rate and local blood flow in the brain using the 2-deoxyglucose- and iodoantipyrine techniques (W. Kuschinsky) . . . . Vasocontrictor and vasodilator substances, their effect on arterial preparations under isometric and constant flow conditions (M. Henn, D. Voth) The influence of peripheral and central monoamine systems on the development of experimental cerebral vasospasm in rats (N. A. Svendgaard, J. Brismar, T. Delgado, N. Diemer) Effects of calcium removal and organic calcium entry blockers on contractile responses in isolated feline cerebral and mesenteric arteries (T. Skarby, K.-E. Andersson, L. Edvinsson, E. D. Hogestatt) Calcium antagonists and smooth muscle (T. Godfraind) Cerebral angiospasm, Ca-current and Ca-antagonists (H. A. Tritthart, H. Tritthart)

105 Ill 121

127

139 153 161

X

Contents

Antivasoconstrictor effects of calcium antagonists: comparative experiments on isolated cerebral vessels, with special references to nimodipine (R. Towart, S.Kazda) Nimodipine for chronic vasospasm due to subarachnoid haemorrhage in primates (B. Weir, F. Espinosa) The effect of the calcium antagonist nimodipine on experimental vasospasm of cat (F. Ulrich, D. Otto, W.J. Bock)

169 177 179

III Clinical pathophysiology of cerebral angiospasm The clinical picture of cerebral vasospasm after subarachnoidal haemorrhage (F. Gerstenbrand, M. Prugger, E. Rumpl, G. Stampfel) 193 Histopathological changes in cerebral vasospasm (J. T. Hughes) 201 Pathological physiology of cerebral blood flow disturbance in vasospasm (A. Baethmann) 209 A review of neurotransmitters and hormones implicated in mediating cerebral vasospasm (M. Wahl) 223 Cerebral ischaemia due to vasospasm after subarachnoidal haemorrhage (A. Hartmann) 231 Spasm of vertebral artery due to blunt mechanical impact: phenomenon and problem (H. P. Schmitt, H. Betz) 241 Pathophysiological and pharmacological aspects of cerebral vasospasm (A discussion of experimental studies) (S. Kazda) 251 Spontaneous regression of carotid stenosis and its differential diagnosis (B. Pohlmann-Eden, H. R. Buchmüller, J. R. Bayerl) 257 Grading of spontaneous subarachnoidal haemorrhage (O.J. Beck) 265 IV Diagnostic procedures and clinical criteria of cerebral vasospasm Neuroradiological aspects of cerebral angiospasm (E. Schindler) Cerebral angiospasm: differential diagnostic considerations (A. Ahyai, K. Rittmeyer, O.Spoerri) Noninvasive transcranial Doppler ultrasound recording in basal cerebral arteries — a new approach to evaluation of cerebrovascular spasm (R. Aaslid, P. Huber, H. Nornes) Flow pattern studies during operation for aneurysm (J. Gilsbach, A. Härders) Angiospasms after aneurysm surgery in the acute stage. Transcranial Doppler ultrasound findings (A. Härders, J. Gilsbach) The ultra short-lived isotope 195m Au — a new diagnostic tool in quantitative cerebral blood flow measurements (P. Lindner, O. Nickel, K. Hahn, D. Eissner)

273 281

287 295 299

303

Contents

Influence of stenotic/occlusive lesions of cerebral arteries and subarachnoidal haemorrhage on lactate and glucose content in lumbar cerebrospinal fluid (CSF) (T. O. Kleine, A. Lutcke) Determination of regional glucose metabolism in patients with ischaemic infarct by positron emission tomography (K. Herholz, G. Pawlik, R. Wagner, K. Wienhard, W. D. Heiss) nrCBF for the assessment of cerebral vasospasm and its therapy (G. Meinig, P. Ulrich, R. Pesch, K. Schiirmann) Serial measurement of regional cerebral blood flow in patients with subarachnoid haemorrhage using 133 xenon inhalation and emission computed tomography (B. Mickey, S. Vorstrup, B. Voldby, H. Lindewald, A. Harmsen, N. A. Lassen) Regional cerebral blood flow measurement in cerebral vasospasm — timing of diagnostic and surgical procedures (J. Bockhorn, A. Brawanski)

XI

309

315 323

331 339

V Therapy of angiospasm — choice of treatment and likely success The incidence of cerebral vasospasm on the timing of surgery during the first week following an aneurysmal rupture (60 cases in a series of 265) (B. Pertuiset, E. Cbaumier, G. Robert, ]. P. Sicbez) Dangers of early operation for prevention of vasospasm in subarachnoid haemorrhage (J. W. F. Beks) Vasospasm, its effect on timing the treatment for aneurysm of cerebral vessels (O. Hey, K. Schiirmann, S. Exner) Treatment of arterial spasm after aneurysmal surgery and subarachnoid haemorrhage with induced hypertension (H. J. Klein, H.-P. Richter, M. Schafer, S.Bien) The use of nimodipine in patients following subarachnoid haemorrhage (B. Weir) Preliminary observations on the use of nimodipine and prostaglandin Ei in acute subarachnoid haemorrhage and ischaemic stroke (H. P. Ammerer, R. Karnik, G. Perneczky) The use of the Ca-antagonist nimodipine in the prevention and the treatment of clinical ischaemia after subarachnoidal haemorrhage and the value of early aneurysm surgery (A. J. M. van der Werf, J. P. Muizelaar, L. M. Hagemann, K. W. Albrecht) A trial with nimodipine, a calcium entry blocker for the prevention and treatment of ischaemic brain damage (H. J. Gelmers) Nimodipine in prevention and treatment of cerebral vasospasm after subarachnoidal haemorrhage (SAH) (L. Russegger, H. Kostron, V. Grunert) . . Tolerance of temporary arterial occlusion in early aneurysm surgery (P. Ljunggren, H. Saveland, L. Brandt)

353 363 367

381 389

391

399 405 413 421

XII

Contents

Prevention of symptomatic vasospasm in patients suffering from subarachnoidal haemorrhage (Preliminary results of an open study) (L. M. Auer, H.J. Reulen, J. Gilsbach, F. Oppel, U. Gröger, A. Härders) Specific calcium antagonism: a new and effective therapy of cerebral vasospasm? (M. R. Gaab, I. Haubitz,']. Bockhorn, A. Brawanski) The treatment of cerebral arterial spasm with nimodipine (Observations based on intra-carotid injections (J. A. Grotenhuis, W. Bettag, B. J. O. Fiebach, K.Dabir) Therapeutical application of the calcium antagonist nimodipine in intracranial vasospasms following subarachnoidal haemorrhage (A. Perneczky, W. Th. Koos, P. Vorkapic, K. Ungersböck) Double-blind study on the use of a calcium antagonist (verapamil) against vasospasm following subarachnoidal haemorrhage (preliminary results) (W. Grossmann, O. Beck, F. Gerstenbrand, G. Paal, E. Rumpl, D. Voth) . . Therapeutic profile of calcium antagonists (H. Eichstädt, M. Gutmann) . .

439 445

453

461

469 475

VI Survey and summary of the meeting (D. Voth)

495

List of contributors Author's index Subject index

507 511 513

I Anatomy of cerebral vessels and regulation of cerebral blood flow

Anatomic variations and anomalies of the cerebral arterial circle of Willis and its central branches"' J. Lang

Introduction The cerebral arterial circle is named after Th. Willis (1621—1675) who also separated diabetes mellitus from diabetes insipidus on account of the sweet taste of urin. The figures shown in his work were taken from Christopher Wren, who dissected a brain with Thomas Willis, published in 1664. Wren injected for the first time fluid in the vessels of an animal while he was the architect of Charles II for whom he built St. Pauls Cathedral and another 53 churches. Even before Galenos of Pergamon (129—199 P. C.) anatomists held the opinion that the internal carotid artery gives off numerous minute branches (Maximum miraculum) between the sphenoid bone and dura mater, which join forming a trunk that supplies the brain. It was believed that the plexus of small arteries produced the spiritus vitalis, which transformed into the spiritus animalis and collected in the ventricles of the brain, from which, it was distributed via nerves to the various body organs. A cranial rete mirabile does in fact, exist in cats, pigs, dolphins and ruminates, but not in man. Berengario da Carpi (1470—1530), an anatomist in Bologna, was the first scientist, who according to Hyrtl (1880), dared to deny the existence of this rete. The cerebral arterial circle was then illustrated by Thomas Willis for the first time.

Circulus arteriosus — development According to Lie (1968), the development of the first aortic arch takes place in an embryo of 1.3 mm, the second at 3 mm, the third, at 4 mm; and at 5—6 mm, the fourth aortic arch develops. In a 3 mm embryo, the rudimentary internal carotid artery (and the rudimentary trigeminal artery) can be detected as a branch of the first aortic arch [20]. After its involution, the rudimentary mandibular artery develops from it. Following the involution of a part of the dorsal descending aorta between 3rd and 4th aortic arch, the flow of blood from the dorsal portion of the 3rd aortic

* This investigation w a s supported by the Deutsche Forschungsgemeinschaft.

4

L. Lang

arch into the internal carotid artery takes place. The internal carotid artery in a 4 mm embryo can be traced in the region of hypophyseal sac dividing into cranial and caudal branch at the level of the primordium of the eye. From the cranial branch, the anterior choroid, the middle cerebral, the rudimentary olfactory and the anterior cerebral arteries arise. The anterior cerebral artery curves medially and is connected with its opposite side by the anterior communicating artery. The caudal branch joins the longitudinal neural artery from which the posterior choroid and tectal branches supply minute branches to the interbrain (diencephalon) and midbrain (mesencephalon). The longitudinal neural arteries arise from the rhombencephalic area, and fuse forming the basilar artery. The communications with the internal carotid artery are rudimentary arteries. After the fusion of vertebral arteries the posterior cerebral artery develops from the posterior communicating artery which however arises from the internal carotid artery. Only at later developing stages, the connection of the posterior cerebral with the vertebral system by the precommunicating segment is established.

Cerebral arterial circle in adults (fig. 1) Internal carotid artery Tode (1787) described for the first time an extremely slender internal carotid artery. Quain (1884) noted the absence of the left internal carotid artery (instead of the carotid artery, two looped small branches of the maxillary artery entered the skull through the oval foramen and rotundum foramen), later however, quite often the absence of internal carotid artery was noted, and finally Turnbull [30] wrote about the lack of the artery in a 81-year old negro. Dilenge [3] using angiography, noted the bilateral agenesis of the internal carotid artery in vivo, Servo [26], reports 35 cases of the complete absence of the internal carotid artery. In case the internal carotid artery is missing or it is hypoplastic, the corresponding internal carotid of the opposite side takes over the blood supply. The anterior communicating artery supplies the anterior region, and occasionally, the posterior communicating artery supplies the middle cerebral territory. After entering into the skull, the internal carotid artery normally gives off one branch from the transversal part downward and two larger cortico-cavernous trunks in the cavernous portion (figs. 2, 3) [17], and then leaves the cavernous sinus before and medially from the anterior clinoid processus. According to Ring and Waddington [23], the subarachnoid segment is between 2.8 and 3.3 mm wide and, in our investigations 13.4 (8.0—18.0) mm long. Then the bifurcation into middle cerebral artery and the anterior cerebral artery takes place. The later branch passes over the optic nerve or optic chiasma and is connected with its opposite side by the anterior com-

Anatomic variations and anomalies of the cerebral arterial circle

5

7-20%

8 3 % Bifurcation 1 5% Trifurcation 2% Tetrafurcalion

Fig. 1

Cerebral arterial circle in adults. Average values of length and caliber (mm), extrem values in parentheses. In case the posterior communicating artery is wider than the precommunical segment of the posterior cerebral artery, it will be classified as the foetal type occurring in 1 2 % of the cases in our investigations.

•; ••• Anast w i t h o p h t h a l m art.

J

s u p hypophys. art.

ant.inf h y p o p h y s art.(Var)-

• R ophthalm

f - --R. maxill •lat. caroticocavern tr

med.tentart (origin isolated)

Mj — /

m e d caroticocavern.art.--/ post caroticocavern.- / ar * /

m

(

r j ' j L^Lf

./**'

M m f f s ^ ^ \ y

f

^ j i ^ ^ ' X rQ Z, ' C

\

"

M' R. inf. ' Rr dòrsi sellae

Anast w i t h ; middle men art""

Rrgangl (V)

Rr clivi - •

petr ant.

Anast contralat.

Rr pori n V ' Rr petr post -' - A n a s t with asc phar art {post.men.art.)

Anast. w i t h - vertebral art. (post. men. art.)

Fig. 2

Vascular network between the internal carotid artery and the cavernous sinus and connections with the medial meningeal artery.

6

L. Lang

municating artery (which is differently wide, variably long and frequently multiple). Due to this vessel the anterior part of the cerebral arterial circle (circulus arteriosus) is completed. In this connection the finding of Bosma [1] is noted, reporting a patient with bilateral visual field disturbances having an infraoptic course of the anterior cerebral artery of the right side (lower bifurcation of the internal carotid artery).

Anterior cerebral artery (see fig. 1) In our investigations the anterior cerebral artery is on the average 2.1 (0.75-3.75) mm wide and 13.5 (8.0-18.5) mm long. According to von Mitterwallner [19] the vessel was not present in 1 . 1 % . After Wollschlager et al. [31] the artery is hypoplastic (1.0 mm or lesser diameter) in 8 . 6 3 % on the right, 4 . 0 9 % left and 3 . 1 8 % bilaterally. In about 1 % the artery is duplicated.

Anterior communicating artery (see fig. 3) According to von Mitterwallner, the anterior communicating artery in 7 4 . 4 % of the cases conforms to figures in text-books, in about 9 % it is doubled, and in about the same percentage V-shaped, Y-shaped or present as a plexus. Riggs and Rupp [22] found that in 9 . 3 % the anterior communicating arteries were hypoplastic. Almost in the same percentage, the main blood supply to the post-communicating part of the anterior cerebral artery occurs via the corresponding artery of the opposite side (hypoplastic pre-communical segment of anterior cerebral artery on one side).

Middle cerebral artery Frequently, the middle cerebral artery is regarded as the continuation of the internal carotid artery. This vessel, in our investigation, is 16.2 (5—24) mm long and 2.7 (1.5—3.5) mm wide. McCormick [18] found that the artery was missing in 0 . 3 % .

Posterior communicating artery (fig. 4) There is no doubt that the posterior communicating artery concerning its width and course is the most variable vessel of the whole cerebral arterial circle. In our investigation, the posterior communicating artery is, on the average, 14 (8—18) mm long and 1.17 (0.5—3.25) mm wide. In case the posterior communicating artery is wider than the precommunical segment of the posterior cerebral artery, it will be classified as the foetal type. This artery, according to our investigations, was found to have a diameter between 0.5 and 1.0 mm in 5 3 % of the cases, in 2 9 % a diameter between 1.0—2.0 mm, in 1 2 % between 2.0—3.25 mm and in 6 % less than 0.5 mm. This vessel according to Wollschlager and Wollschlager was absent in 0 . 9 % right and 0 . 4 5 %

Anatomie variations and anomalies of the cerebral arterial circle

7

left, and in our investigations in about 1%. We regarded the vessels having the width 2.0—3.25 mm as the foetal type of posterior communicating artery. These occurred in 12% of the cases in our investigations. Saeki and Rhoton [24] give a figure of 46% as foetal types (without width measurements). According to these authors, 32% (26% unilateral and 6% bilateral) the posterior communicating arteries were hypoplastic, having a diameter of less than 1 mm. Using this definition for the hypoplastic posterior communicating arteries, the results of our investigations reach 5 9 % . The posterior communicating artery arises 8.23 (5.0—13.0) mm proximal to the bifurcation of the internal carotid artery and 3.47 (1.5—7.0) mm proximal to the anterior choroid artery, in 58.63% of the cases on the inferior and posterior, in 28.50% on the medial and in 11.51% on the lateral perimeter. Von Mitterwallner has empha-

1 Fig. 3

2

3

U

5

6

7

Bifurcation (island) of the precommunicating branch of the anterior cerebral artery. 1. Anterior cerebral artery; 2. Optic tract; 3. Bifurcation; 4. Optic chiasm (mm-paper); 5. Anterior communicating artery and left anterior cerebral artery; 6. Posterior communicating artery; 7. Internal carotic artery.

8

L. Lang

1 2 Fig. 4

3

4

5

6

7

8

9

Posterior communicating artery and inferior diencephalic branches. 1. Superior cerebellar artery; 2. Posterior cerebral artery (postcommunicating part); 3. Posterior communicating artery; 4. Inferior diencephalic branches; 5. Inferior posterior diencephalic branch (R. interpeduncularis); 6. Mamillary body (mamillary artery) and basilar artery; 7. Optic nerve and superior hyophyseal artery; 8. Precommunicating part of posterior cerebral artery and artery of lamina tecti, traversing n. Ill (displaced backwards); 9. Posterior communicating artery, embryonic type.

A n a t o m i e variations and anomalies of the cerebral arterial circle

9

sized that very short posterior communicating arteries were found when the subarachnoideal segment of the internal carotid artery was longer. The origin of the vessel lies usually in the lower and medial perimeter of the internal carotid artery. Infundibular widenings at branching points For the first time Saltzman [25] pointed out, that the occasional occurrence of infundibulum-like dilatation (infundibular widenings) at the origin, which according to Wollschlager et al. [31] occurred in 5.9% right and 8.18% left, and in 3.63% both sides. I found these widenings in 11.4%. These dilatations are not aneurysms and present at the origins of the anterior cerebral artery, the superior cerebellar artery and the posterior inferior cerebellar artery [31].

Posterior cerebral artery, precommunical segment In our investigations, the precommunical part of the posterior cerebral artery is found to be 6.3 (3.0—9.0) mm long and 2.11 (0.7—3.0) mm wide. It receives its blood supply from the basilar artery which is, on the average, 3.47 (1.50-7.0) mm wide. Its bifurcation lies radiologically 10.6 (6.0—17.0) mm away from the posterior clinoid process [5]. In rare cases I found fenestrations of this part of the circle. In one of our cases arose the lateral occipital artery from the middle cerebral artery [14].

Cerebral arterial circle, medical implications The medical significance of the basal vascular network can be characterized as follows. Blood distribution Fawcett and Blachford [4], examining 700 specimen, concluded that a completely developed arterial circle exists in about 96% of the cases, although some partial segments are variable in size. Muscle wall of the cerebral arteries and aneurysms (figs. 5, 6 and 7) The cerebral arterial circle, its larger branches (and those from the vessels of vertebral circulation), especially at areas of supply are prone to develop smaller and larger aneurysms. Since the tunica media of the larger and smaller cerebral arteries has circular muscle fibers, an incomplete arrangement of these fibres mainly at the rightangled branching, of the vessels can lead to muscle lacunae and subsequent wallweakness and aneurysms. It has to be emphasized, that the muscle-wall of the subarachnoidal cerebral arteries is much thinner than on any of the comparable arteries in the body [8, 9]. It has been found that about 85% of cerebral aneurysms

10

L. Lang

(20 muscle cells)

A. mesenterica sup. (35 muscle cells)

Aa. basilar is et mesenterica sup. (same diameter) Fig. 5

Thickness of tunica media et adventitia, a comparison between two arteries of the same width.

lie in the anterior, 1 5 % in the posterior portion of the arterial circle (vertebral circulation system). Moreover, aneurysms are observed at the branching regions of the arteries such as pericallosal artery, middle cerebral artery and posterior cerebral artery. Rami centrales From the cerebral arterial circle, numerous small arteries arise which pierce the cerebral matter from its basal aspect. These are the central rami. The basal central rami of the middle and anterior cerebral arteries supply the lenticular nucleus and

Anatomic variations and anomalies of the cérébral arterial circle

11

A. cerebri ant. (16 muscle cells) 140pm_ ^ ^ 1 1 0 p m

^

Acarotis int, p. subarachnoidealis (20 muscle ceils)

A. carotis int, p.cavernosa (22 muscle cells)

A. carotis int,p.cervicalis asc. (55 muscle cells) Fig. 6

Thickness of arterial walls of the internal carotic artery and the anterior cerebral artery. N o t e the number of muscle cells.

nucleus caudatus, as well as the internal capsule (fig. 8). The central vessels e.g. Lang [11] and Lang and Brunner [16] are the rami diencephalici and supply the hypothalamic and thalamic regions, the rami diencephalici inferiores posteriores the mesencephalon. It has to be emphasized that the blood circulation of the interbrain (diencephalon) not only arises from the branches of cerebral arterial circle but also

12

L. Lang

from branches of the superior cerebellar artery and the tectal artery (fig. 9) which supply the midbrain (mesencephalon) as well. From the anterior choroidal artery branches emerge, the rami diencephalici. This vessel originates, according to our investigations, in 96% of the cases from the internal carotid artery and in 2 % from the posterior communicating artery. In 2% of the cases this vessel has a double origin, one arising from the internal carotid artery and the other from the posterior communicating artery (fig. 9). The origin of the anterior choroid artery is located 2.9 (0.5—5.0) mm proximally of the carotid bifurcation. The vessel is 0.77 (0.4—1.25) mm wide and minute branches are given of to the interbrain (diencephalon), the optic tract, and the posterior part of the internal capsule (Radiatio optica). Parts of the telencephalon are also supplied by the anterior choroidal artery, especially the anterior part of the optic radiation. The

1 Fig. 7

2

Origin of the peduncular branch emerging from the bifurcation area of the basilar artery. 1. Wall of basilar artery; 2. Origin zone of the interpeduncular branch.

Anatomie variations and anomalies of the cerebral arterial circle

13

Ant. recurr. art. (Heubner) origin relating to ant.comm. art.(%)

diameter (mm) (mean)

Central rami of middle cerebral art. group number diameter{mm) in% (mean) (mean) - med.71 1,8(1-4) 0.33(0.12-1.25) - mid 86 2.2(1-8) 0,44(012-2.00) - Iat.100 4,1 (1-9) 052(0.12-1.75)

Fig. 8

Central branches of the middle cerebral artery and the anterior recurrent artery (Heubner), origin and diameter.

vallecula (= recess between frontal and temporal brain) is supplied by the direct branches of the internal carotid artery in 4 6 % ; also the uncus, gyri parahippocampalis and amygdaloid nucleus (30%). For further details of the central branches, consult the tabular summaries and figures. Some branches of the internal carotid artery and the middle cerebral artery, the posterior choroidal arteries and the posterior cerebral artery can supply areas of the diencephalon. Access to the hypophyseal region and central rami In the neurosurgical approach to the hypophyseal region (hypophyseal tumours, aneurysms, etc.), the central rami of the cerebral arterial circle should be preserved. The anterior inferior diencephalic rami from the anterior cerebral artery and the anterior communicating artery supply the fronto-medial hypothalamic region. In this area, a hypothalamic temperature control center is located and its damage may result in the loss of this control. The inferior diencephalic rami from the posterior communicating artery and the internal carotid artery supply the middle hypothalamic and thalamic regions. The posterior inferior diencephalic rami from the posterior cerebral, basilar, superior cerebellar and tectal arteries supply besides the midbrain, parts of the posterior inferior diencephalon. The posterior diencephalic rami, the posterior choroidal rami and the thalamogeniculate rami from the posterior cerebral artery supply the posterior and superior regions of the diencephalon. The middle cerebral artery was found to be 16.2 (5.0—24.0) mm long and 2.7 (1.5—3.5) mm wide. The diameter was on the average between 2.5 and 3.0 mm. Usually the anterior temporal branch, the orbito-frontal branch, the temporo-polar branch, as well as minute branches emerge from the middle cerebral to supply the temporal and orbital cortical region of the transitional zone between the frontal and

14

L. Lang

NwL

f T* Safl * 5s-

Fig. 1 Whole-mount preparations of rabbit anterior spinal artery. a) Labelled histochemically for acetylcholinesterase. A sparse innvervation is present, (arrowheads). Magnification X210. b) Labelled immunohistochemically for serotonin. A net of very fine fibres is positive. Magnification X440. c) Labelled immunohistochemically for V.I.P. A net of very fine fibres is positive. Magnification X720. d) Labelled immunohistochemically for substance P. A net of very fine fibres is positive. Magnification X720.

The innervation of the cerebral nervous system vasculature in the rabbit

.2

Stretch preparations of rabbit spinal cord (lumbar) pia mater, containing spinal cord veins and fine arteries. a) Labelled immunohistochemically using antibody specific for acetylcholine receptor. Dense positive staining of branching structures is present on this vein (arrows). Magnification X 160. b) Labelled histochemically for acetylcholinesterase. Positive reaction is present in identical structures to those positive in a) arrows). An artery (arrowheads) nearby lacks positive structures. Magnification x 250. c) Labelled immunohistochemically for serotonin. A net of very fine fibres is positive. Magnification x 1024.

46

P. L. Debagge, D. Dwyer and R. Meyermann

The spinal cord veins (thoracic, lumbar) were heavily labelled both by the antiacetylcholine receptor antibody (fig. 2 a), and also heavily for acetylcholinesterase (fig. 2 b). The same characteristic branching structures were stained in both cases, and even the fine granularities of the stained structures were identical. We also observed identical immunohistochemical labelling by an IgG2b monoclonal antibody of non-acetylcholine receptor specificity. Some spinal cord arteries were not labelled by these reagents (fig. 2 b). A fine net of positive serotoninergic fibres was noted in the spinal cord veins (fig. 2 c). The labelling by the anti-acetylcholine receptor antibody could be followed down into the radial vessels in frozen sections taken from the spinal cord.

Discussion Our preliminary results demonstrate the mode of innervation in the arterial vasculature of the rabbit spinal cord, which can be related to a wide range of neurotransmitters. A complex neuronal control of the spinal cord blood flow present appears to be possible in this species. Similarly to the cerebral basilar artery, the anterior spinal artery receives aminergic, (sparse) cholinergic, and peptidergic innervations. We failed to show in this study that the spinal cord veins receive peptidergic innervation, either because these transmitters are absent, or present in low concentrations only. A characteristic morphology was associated with the different transmitters, consistent with a multiple vascular innervation. The presence of acetylcholinesterase-positive structures in the walls of the spinal cord veins in rabbits is in contrast to their absence in the spinal cord veins of cats [7]. This may well represent a true species difference, since the basic histochemical procedure used in both studies was the same, and since Itakura's (slightly modified) method revealed such fibres in the spinal artery. The similarity of the immunohistochemical staining for acetylcholine receptor with the histochemical staining for acetylcholinesterase enzyme is at first sight a strong evidence for true cholinergic innervation of spinal cord veins in the rabbit. The similarity of the structures stained with these very different procedures is striking, and visible even at the granular appearance of the staining. Since the antibody is specific for a muscle receptor this would favour a nicotinic innervation and not the (expected) muscarinic innervation. A nicotine-induced and innervation-dependent dilation of canine cerebral arteries was reported by Toda [15], though it could not be demonstrated that this was a typical cholinergic transmission. However, an antibody of different specificity, unrelated to acetylcholine receptor, but of the same subclass (IgG2b) as the antireceptor antibody is found to be bound to exactly the same structures found by us in veinous preparations. This indicates a binding not caused by immune specificity, and may represent a feature peculiar to this subclass of an-

47

The innervation of the cerebral nervous system vasculature in the rabbit

tibodies. This is a finding of some interest, in its relation to a structure which is possibly the sub-synaptic membrane of a cholinergic synapse, as defined in terms of acetylcholinesterase histochemistry. In conclusion, our studies demonstrate the feasibility of mapping immunohistochemically various types of innervation throughout the vasculature of the central nervous system. We hope that a systematic mapping, when fully completed in healthy animals, will be a usefull model for the cerebrovascular innervation in primates and man.

References [1] Ando, K.: A histochemical study on the innervation of the cerebral blood vessels in Bats. Cell Tissue Res. 2 1 7 , 5 5 - 6 4 (1981). [2] Duckies, S. P. and S. I. Said: Vasoactive intestinal peptide as a neurotransmitter in the cerebral circulation. Eur. J . Pharmacol. 78, 3 7 1 - 3 7 4 (1982). [3] Dwyer, D. S., R. J . Bradley, C. K. Urquhart and J . F. Kearney: An enzyme-linked immunoabsorbent assay for measuring antibodies against the muscle acetylcholine receptor. J . Immunol. Methods 5 7 , 1 1 1 - 1 1 9 (1983). [4] Edvinsson, L., M . Lindwall, K. C. Nielsen and C. Owman: Are brain vessels innervated also by central (non-sympathetic) adrenergic neurons? Brain Res. 6 3 , 4 9 6 - 4 9 9 (1973). [5] Edvinsson, L. and R. Uddman: Immunohistochemical localization and dilatory effect of substance P on human cerebral vessels. Brain Res. 2 3 2 , 466—471 (1982). [6] Hirst, G. D. S., T. O. Neild and G. D. Silverberg: Noradrenaline receptors on the rat basilar artery. J . Physiol. 3 2 8 , 3 5 1 - 3 6 0 (1982). [7] Itakura, T.: Aminergic and cholinergic innervations of the spinal cord blood vessels of cats. J . Neurosurg. 5 8 , 9 0 0 - 9 0 5 (1983). [8] Iwayama, T., J . B. Furness and G. Burnstock: Dual adrenergic and cholinergic innervation of the cerebral arteries of the rat. An ultrastructural study. Circ. Res. 2 6 , 635—646 (1970). [9] Karnovsky, M . S. and L. Roots: A "direct-coloring" thiocholine method for cholinesterases. J . Histochem. Cytochem. 12, 2 1 9 - 2 2 1 (1964). [10] Koelle, G. B.: Cytological distributions and physiological functions of cholinesterase. In: Handbuch der

Experimentellen

Pharmakologie

XV.

Cholinesterases

and

Anticholinesterase

Agents,

pp. 1 8 7 - 2 9 8 . Edited by G. B. Koelle. Springer-Verlag, Berlin 1963. [11] Lee, TJ-F.: Ultrastructural distribution of vasodilator and constrictor nerves in cat cerebral arteries. Circ. Res. 4 9 , 9 7 1 - 9 7 9 (1981). [12] Lee, TJ-F., W. R. Hume, C. Su and J . A. Bevan: Neurogenic vasodilation of cat cerebral arteries. Circ. Res. 4 2 , 5 3 4 - 5 4 2 (1978). [13] Mitchell, G., D. Mitchell and C. Rosendorff: Vasodilator mechanism of the intrecerebral (nonsympathetic) adrenergic pathway. Cardiovasc. Res. 12, 42—48 (1978). [14] Sternberger, L. A.: Immunocytochemistry. J . Wiley and Sons, New York 1979. [15] Toda, N.: Nicotine-induced reaction in isolated canine cerebral arteries. J . Pharmacol.

193,

3 7 6 - 3 8 4 (1975). [16] Yamamoto, M . , H. W. M . Steinbusch and T. M . Jessell: Differentiated properties of identified serotonin neurons in dissociated cultures of embryonic rat brain stem. J . Cell. Biol., 9 1 , 142—152 (1981).

Electrical and chemical control of activation processes in vascular smooth muscle* K. Golenhofen

Introduction Vascular smooth muscle is influenced by many external factors, most of which mediate their effects on the cell through chemical messengers (hormones, transmitters etc.) which usually act on receptors at the cell membrane (Ri . . . R3 in fig. 1). Beyond the level of the receptors, the "inner life" of the cell begins, and it is only this part which forms the subject of this article. The term "activation processes" describes those processes which control the activation of the contractile proteins. These activation processes are located in the cell membrane, as illustrated in figure 1, and they produce their effects by changing the chemical milieu in the interior of the cell, particularly by changing the concentration of free calcium ions.

Differentiation of phasic and tonic activation processes Vascular smooth muscle possesses an activation process which is somewhat similar to that of skeletal muscle: the cell membrane generates an action potential (spike) which induces a release of calcium into the cytoplasm, and this increase of calcium concentration triggers the contraction. During the initial stages of smooth muscle electrophysiology, the concept was developed that spike generation was a general accompaniment of smooth muscle activation. However, this concept had to be corrected and some examples how the complex activation concept illustrated in figure 1 developed during the last 20 years. First of all, the smooth muscle spike is different in its mechanism from spikes in nerve and skeletal muscle. The nerve spike is produced by a sodium system in the cell membrane. The smooth muscle spike, however, is dependent on calcium ions and is called a "calcium spike". Part of the evidence for the calcium nature of the smooth muscle spike is the fact that calcium inhibitors such as nifedipine are able to suppress selectively the smooth muscle spike (and not the nerve spike). * The work was supported by grants from the Deutsche Forschungsgemeinschaft and the Fritz-ThyssenStiftung.

50

K. Golenhofen CALCIUM

Fig. 1

ACTIVATION

IN S M O O T H

MUSCLE

Differentiation of phasic and tonic activation in smooth muscle. Simplified diagram. (After Golenhofen, 1984 [11].)

This selective spike suppression using drugs from the calcium antagonist group (calcium entry blockers, calcium inhibitors) offered a new tool for smooth muscle analysis. For example, after blockade of the spike mechanism, it was possible to test whether smooth muscle was able to produce contraction by another mechanism. An example of such a test is given in figure 2. In guinea-pig portal vein the spontaneous rhythmical activity (fig. 2 A) is associated with fluctuations of spike discharges. After application of nifedipine the spike discharges are suppressed, and the spontaneous activity is abolished as well. The disappearance of the spontaneous activity is illustrated in figure 2 B. Noradrenaline is unable to produce a re-appearance of spike discharges and phasic spontaneous activity. It is, however, still able to produce a tonic activation not associated with spike discharges but by a depolarization of the cell membrane (fig. 2 B). This spike-free tonic contraction, which was 58% of the control response in the case illustrated in figure 2, is not significantly reduced by increasing further the nifedipine concentration by a factor of 10 or 100 (fig. 2 C). Only papaverine was able to suppress the nifedipine-resistant tonic contraction. The fact that a part of the activation can be suppressed by selective antagonists indicates that at least two different activation processes must exist in smooth muscle cells. In comparative studies with many types of smooth muscle we have observed that the nifedipine-sensitive (spike-associated) process is preferentially used for producing phasic activity, and the nifedipine-resistant process always produces tonic

Electrical and chemical control of activation processes in vascular smooth muscle

51

A. CONTROL NORADRENALINE

C.

Fig. 2

NIFEDIPINE

Mechanical activity of an isolated guinea-pig portal vein. A: Normal spontaneous phasic activity and a control response to cumulative application of noradrenaline (NA). B: Suppression of spontaneous activity after application of nifedipine. Reduced response to NA of purely tonic character. C: The "nifedipine-resistant" tonic NA response is not significantly reduced by further increase of the nifedipine concentration to 10~ 6 or 10~ 5 mol/1. (From Golenhofen, Wagner and Weston, 1977 [17].)

activity. This is the reason for using the symbols P and T to designate the two processes shown in figure 1 [8, 10, 11]. During blockade of the P system, the activation via the T system is usually associated with a spike-free depolarization. However, if the cells are completely depolarized by application of a potassium-rich solution, the tonic activation via the T system can still be elicited without any change of the membrane potential. This could be shown as well for guinea-pig portal vein [12] as for preparations from the gastric fundus [13,14]. This indicates that the T system is, at least in some types of smooth muscle, predominantly under chemical control ("pharmaco-mechanical coupling" after Somlyo; "non-electrical activation" after Bohr, see [1]). The term "chemical control" used in figure 1 includes spike discharges as well as spike-free depolarizations.

52

K. Golenhofen

"Calcium-free" contractions It is now assumed today that calcium ions are the link which mediate the excitation to the contractile proteins. However, some new observations indicate that other substances may also be involved in the normal process of excitation-contraction coupling. In smooth muscle preparations from canine gastric fundus, where the T system is strongly pronounced, we have observed that part of the nifedipine-resistant tonic contraction could be elicited over hours in Ca-free solution [13, 14]. In the example shown in figure 3 the extracellular calcium concentration was reduced below 1 0 - 8 mol/1 by application of EGTA. Even under these conditions a tonic contraction could repeatedly be elicited over a period of several hours without significant reduction of its size. It is difficult to imagine that these contractions are triggered by an intracellular fraction of calcium without any loss of calcium by diffusion through the cell membrane. We assume, therefore, that other substances are involved in triggering the contraction, particularly in those contractions which are predominantly controlled by a T system. Riiegg and Paul [20] have recently reported that in skinned preparations from carotid artery the calcium sensitivity is strongly altered by calmodulin, and they concluded "that relaxation of contraction in vascular smooth muscle cannot be described solely in terms of decreasing cytoplasmic free Ca 2 + . Changes in the sensitivity of the contractile proteins at a given Ca 2 + concentration are also potential mechanisms for vasodilatation."

N I F E D I P I N E 10~ 6 mol/1, K * H 3 m m o l / l ACETYLCHOLINE

I

5

min

10

HQ .WWWWWM ,

T I M E IN C a - F R E E

Fig. 3

65

I

70

I I

75 85

I

90

min

,

95

T I M E IN C a - F R E E , E G T A 2 m m o l / l

Contraction of a circular muscle strip from the fundus region of canine stomach. Recording of length under auxotonic (near-isotonic) conditions at little preload (1 mN/mm 2 ). The preparation was depolarized with potassium-rich solution and treated with nifedipine. The first acetylcholine (ACh) application was made a few minutes after incubation in calcium-free solution and induced a strong initial contraction of nearly normal size which decreased rapidly to a lower level. After application of calcium (2.5 mmol/1) the contraction returned to the normal value. Second and third parts: During long-term incubation in calcium-free solution (Ca concentration reduced below 1CT8 mol/1 by application of EGTA 2 mmol/1) a contraction could still be elicited by ACh which was 30 to 40% of the control response. (From Golenhofen et al., 1982 [14].)

Electrical and chemical control of activation processes in vascular smooth muscle

Fig. 4

53

Development of spontaneous activity of spiral strips from canine coronary arteries after incubation in physiological salt solution and pre-stretch to about in situ-tension (Stretch). Application of a potassium-rich solution (K + 40 mmol/1) induced a nearly maximum contraction of the strips. The zero value of active tension development was determined by application of nitroprusside sodium (10~ 5 mol/1) at the end of the experiment. A: Preparation from a small coronary artery (diameter 1.5 mm), branch of the R. circumflexus as indicated in the diagram, from a normal heart. Development of weak spontaneous tonic activity (basal tone). B: Strip from a collateral artery, about 1 mm diameter, localization as indicated, excised 2 months after progressive occlusion of R. circumflexus and A. cor. dextra (the arrows mark the localization of the implanted ameroid constrictors). Development of strong spontaneous phasic activity which reached 80% of the potassium response. (From Golenhofen et al. 1981 [15], modified.)

54

K. Golenhofen

Variations between different types of blood vessels Activation of vascular smooth muscle is a complex interaction between many components. These various components exist in different reaction patterns in different types of smooth muscle, and this is the reason for the great diversity in the smooth muscle system. As a general rule one can say that the T system is particularly represented in the aorta and large arteries, and the P-T-relation shifts towards the P system in direction of smaller arteries and veins. Furthermore, organ specific differences exist between arteries of equal size, and finally species differences are observed. Generally the P system is more dominant in smaller mammals than in larger species. The fact that smaller mammals such as rats and guinea-pigs are preferred for experimental studies, has lead to an undue emphasis being attributed to the significance of spike discharges in the activation processes of smooth muscle. The great diversity of vascular smooth muscle responses can be seen from recent studies in coronary arteries [9]. Isolated spiral strips from canine coronary arteries usually develop a pronounced spontaneous activity which under normal conditions is always tonic in character (basal tone, fig. 4 A). In human coronary preparations, however, a strong phasic spontaneous activity is observable which can be classified as minute-rhythm (fig. 5). Based on similar observations, Ross et al. [19] have suggested that canine coronary

after death). The active tension is calibrated as a percentage of the control response to application of high-potassium solution ( K + 4 0 mmol/1). Vaso-active substances were applied as indicated. Suupression of the phasic activity by nifedipine. The nifedipine-resistant tonic activity w a s suppressed by nitroprusside sodium (NP 1 0 ~ 5 mol/1). (From Golenhofen, 1 9 8 0 [9].)

Electrical and chemical control of activation processes in vascular smooth muscle

55

arteries may not be an adequate model for human coronary circulation. Such a generalization, however, is not justified. In dogs undergoing progressive coronary occlusion a state of phasic hyperactivity similar to the spontaneous activity of human coronary arteries is present. This introduces a new parameter into the diversity of vascular smooth muscle: the fundamental characteristics of a smooth muscle cell are altered in different functional conditions and the same vessel of a particular species may not necessarily a universal model, for the behaviour of that vessel changes in pathological conditions. Drug responses are also modified under changed conditions, as shown in figure 6 for coronary arteries. Application of TEA (tetraethylammonium) induces in coronary arteries a type of activity which can serve as a model for the state of phasic hyperactivity. We have compared the effects of various vasodilator drugs on a TEAinduced activation with the effects on a noradrenaline-induced activation (during blockade of the adrenergic beta receptors). Nifedipine was about ten times more NIFEDIPINE

CORONARY

Fig. 6

ARTERY,

(NIF)

DOG

/ NITROGLYCERIN

(NG)

,

5 mi n

Mechanical activity (isometric recording) of four spiral strips (a . . . d) from normal canine coronary arteries, all from the same heart. The localization of the preparations is marked in the insert. Preparations a) and b) were stimulated with T E A (tetraethylammonium, 10 mmol/1, and in addition indomethacin 2 - 1 0 " 6 mol/1), the preparations c) and d) with noradrenaline (NA, 10~ 5 mol/1), blockade of the beta receptors with propranolol 10~ 5 mol/1). Application of nifedipine to the preparations a) and c), and of nitroglycerin to b) and d). In the later part of the experiment nitroglycerin ( N G 1 0 - 5 mol/1) was applied to all preparations, and nifedipine also to b) and d). Finally nitroprusside sodium (NP 1 0 " 4 mol/1) was applied to determine the zero value of active tension. (After Weinheimer, Golenhofen and Mandrek, 1983 [22], unpublished figure.)

56

K. Golenhofen

potent than nitroglycerin in suppressing the TEA-activation. Nitroglycerine, on the other hand, was about ten times more potent than nifedipine in suppressing the noradrenaline-induced activation. Such results could explain the clinical observation that in some types of angina pectoris (e.g. Prinzmetal's variant angina) nifedipine is more effective, whereas nitroglycerine is more effective in other types. A differentiation of the activation processes is, therefore, a necessary procondition if we want to test questions of clinically relevant problems.

Technique of video-angiometry Finally a methodological progress has to be mentioned which is of particular interest for vasospasm research. Although studies using helical strips from isolated blood vessels can be quite useful for analysing some basic processes, the value of such studies is limited in respect of normal blood vessel function in situ. We have therefore further developed the technique of video-angiometry and applied this to the measurement of the diameter of perfused blood vessel segments (fig. 7). The perfused segment is observed with a video camera, and the video signal is stored on a video recorder. One line of the video picture is connected with an angiometer for diameter analysis. The light-dark-contrast at the borders of the segment is used to switch a high frequency oscillator on and off, and the number of oscillations supply a digital

LINE

Fig. 7

Recording of the diameter of perfused blood vessel segments by video-angiometry, diagram. (After Golenhofen, Mandrek and Wiegand, 1979 [16], from Wiegand, 1983 [24].)

Electrical and chemical control of activation processes in vascular smooth muscle

Fig. 8

57

Monitor picture during video-angiometry. The upper light line represents the measuring signal. The two other light lines can be adjusted manually and are used to mark reference values of the diameter for a better optical control. (After Golenhofen, Mandrek and Wiegand, 1979 [16], unpublished figure.)

signal proportional to the vessel diameter. For direct optical control the measuring signal is fed back to the monitor as a bright line (example in fig. 8), whilst two additional lines in the monitor picture are adjusted manually and are used to mark the initial diameter and a further reference value for continuous optical control. This technique allows a continuous recording of the vessel diameter with only little disturbance to the vessel. The endothelium of the segment remains unaltered which is important in views of recent observations. One other advantage of this technique is the good spatial resolution. The constrictor responses of vascular segments are not always homogenous and are sometimes confined to a small portion of the segment. Video-angiometry allows such localised spasms to be observed. The stored responses can be repeatedly replayed for diameter analysis, and the measuring system can be adjusted to another location with each replay. An example of this is given in figure 9. Here the response of a coronary segment was analysed at seven different locations allowing the production of a response profile for the whole segment length of 30 mm. More details about blood vessel physiology are found in the following reviews: 1—7, 11, 18, 21, 23.

58

K. Golenhofen

CORONARY

ARTERY

( S E G M E N T , R A M . C I R C U M F L E X ), D O G

o

o

o

o

o — 100'/.

90% O DIAMETER VALUES BEFORE K'-APPLICATION (REFERENCE) • DIAMETER VALUES AFTER 20min K4-APPLICATION

807. P O S I T I O N OF BRANCHES

/ \

10 20 D I S T A N C E FROM B I F U R C A T I O N Fig. 9

(mm)

707. 30

Non-homogeneous constrictory response of a perfused segment from a canine coronary artery (Ramus circumflexus) to application of potassium-rich solution. T h e diameter of the segment was analysed at 7 locations using the video-angiometry. (From Wiegand, 1 9 8 3 [24].)

References [1] Bohr, D . F., A. P. Somlyo and H . V. Sparks (eds): Vascular smooth muscle. H a n d b o o k of Physiology, Sect. 2, Vol. 2 . American Physiological Society, Bethesda, Maryland 1 9 8 0 . [2] Bolton, T . B.: Mechanisms of action of transmitters and other substances on smooth muscle. Physiol. Rev. 5 9 , 6 0 6 ( 1 9 7 9 ) . [3] Bülbring, E., A. F. Brading, A. W . Jones and T . Tomita (eds): Smooth muscle. Edward Arnold, London 1 9 7 0 . [4] Bülbring, E., A. F. Brading, A. W . Jones and T . T o m i t a (eds): Smooth muscle, an assessment of current knowledge. Edward Arnold, London 1 9 8 1 . [5] Bülbring, E. and M . F. Shuba (eds): Physiology of smooth muscle. Raven Press, N e w Y o r k 1 9 7 6 . [6] Casteels, R . , T . Godfraind and J . C. Rüegg (eds): Excitation-contraction coupling in smooth muscle. Elsevier/North-Holland, Amsterdam, N e w Y o r k , O x f o r d 1 9 7 7 . [7] Fleckenstein, A.: Calcium antagonism in heart and smooth muscle. J o h n Wiley and Sons, N e w Y o r k 1983. [8] Golenhofen, K.: Die myogene Basis der glattmuskulären Motorik. Klin. Wschr. 5 6 , 2 1 1 - 2 2 4 (1978). [9] Golenhofen, K.: M o t o r i k der Blutgefäße und Probleme der koronaren Zirkulation. Ber. PhysicoMedica (Würzburg), 8 7 , 1 8 3 - 1 9 2 ( 1 9 8 0 ) . [10] Golenhofen, K . : Differentiation of calcium activation processes in smooth muscle using selective antagonists. In: E . Bülbring et al. (eds.), Smooth muscle, pp. 1 5 7 - 1 7 0 . Edward Arnold, London 1981. [11] Golenhofen, K . : Grundlagen der M o t o r i k : Quergestreifte und glatte Muskulatur. In: J . Haase (ed.): Neurophysiologie, 2 . Auflage, pp. 53—94. Urban 8c Schwarzenberg, München 1 9 8 4 .

Electrical and chemical control of activation processes in vascular smooth muscle

59

[12] Golenhofen, K., N. Hermstein and E. Lammel: Membrane potential and contraction of vascular smooth muscle (portal vein) during application of noradrenaline and high potassium, and selective inhibitory effects of iproveratril verapamil). Microvasc. Res. 5, 73—80 (1973). [13] Golenhofen, K., J. Hohnsbein, J. Lukanow and K. Mandrek: A new physiological mechanism for the control of contractile tone in mammalian smooth muscle. Pfliigers Arch. 382, Suppl., R. 25 (1979). [14] Golenhofen, K., J. Hohnsbein, E. Lammel, J. Lukanow, and K. Mandrek: Contractile tone of canine gastric fundus: Evidence for chemical, non-electrical control. In: M. Wienbeck (ed.): Motility of the digestive tract, pp. 95—102. Raven Press, New York 1982. [15] Golenhofen, K., K. Mandrek, W. Schaper, G. Weinheimer and W. Wiegand: Mechanical activity of isolated canine coronary arteries after coronary occlusion. Basic. Res. Cardiol. 76, 480—484 (1981). [16] Golenhofen, K., K. Mandrek and W. Wiegand: Continuous recording of length and diameter in isolated segments of coronary arteries. Pfliigers Arch. 382, Suppl., R 8 (1979). [17] Golenhofen, K., B. Wagner and A. H. Weston: Calcium systems of smooth muscle and their selective inhibition. In: R. Casteels (ed.), Excitation-contraction coupling in smooth muscle, pp. 131-136. Elsevier/North-Holland Biomedical Press, Amsterdam 1977. [18] Kalsner, S. (ed.): The coronary artery. Croom Helm Ltd., London 1982. [19] Ross, G., E. Stinson, J. Schroeder and R. Ginsburg: Spontaneous phasic activity of isolated human coronary arteries. Cardiovasc. Res. 14, 613—618 (1980). [20] Riiegg, J. C. and R. J. Paul: Vascular smooth muscle. Calmodulin and cyclic AMP-dependent protein kinase alter calcium sensitivity in porcine carotid skinned fibers. Circ. Res. 50, 394—399 (1982). [21] Vanhoutte, P. M. and D. F. Bohr: Calcium entry blockers and the cardiovascular system. Fed. Proc. 40, 2851-2881 (1981). [22] Weinheimer, G., K. Golenhofen and K. Mandrek: Comparison of the inhibitory effects of nifedipine, nitroglycerin and nitroprusside sodium on different types of activation in canine coronary arteries, with comparative studies in human coronary arteries. J. Cardiovasc. Pharmacol. 5, 989-997 (1983). [23] Weiss, G. B. (ed.): New perspectives on calcium antagonists. American Physiological Society, Bethesda, 1981. [24] Wiegand, W.: Untersuchungen zur Motorik von Koronararterien. Inaugural-Dissertation, Marburg 1983.

Experimental noradrenaline- and hydroperoxide induced contractions in segments of carotid arteries H. Heinle, D. Kling, E. Betz

Introduction Since it is not possible to study the cause of vasospasm in man it is necessary to elaborate experimental models. The results of these findings when compared with observations in human pathology reveal their usefulness for further experimental studies. This contribution deals with two different types of in vitro experiments on the common carotid artery in rabbits and show, 1. that experimentally induced atherosclerosis increases the reactivity of the vessel wall towards noradrenaline, 2. that exogenous hydroperoxides probabely important intermediates in the genesis of vasospasms after subarachnoid haemorrhage [6] evoke reversible contractions which need considerably less extracellular Ca 2 + than other spasm-inducing stimuli.

Materials and methods For all experiments common carotid arteries of two groups of male New Zealand rabbits (2.5-3.5 kg body weight) were used. Group I contained 9 animals in which atherosclerotic lesions within the carotid artery were induced by daily repeated, local transmural electric stimulation according to Betz and Schlote [1]. Group II consisted of 8 normally fed, nonstimulated animals. After 4 weeks, the stimulated and nonstimulated contralateral carotid artery of the animals of group I were excised. The vessel segments were further dissected in 4 mm long rings, mounted in a measuring chamber equipped for the registration of isometric contractions as described [5]. The chamber (volume 8 ml) was perfused by oxygenated Tyrode solution (composition below). Noradrenaline (NA) was applied in a concentration range of 10 - 9 —10 - 3 mol/1 and the circumferential wall force was recorded [10], The experiments of group II were conducted in a similar manner. The vessel segments were mounted in the measuring chamber, superfused by Tyrode solution

62

H. Heinle, D. Kling and E. Betz

(composition in mmol/1: NaCl, 118; KC1,5.32; CaCl 2 -2 H z O, 2.53; MgS0 4 -7 H 2 0 , 1.19; N a H 2 P 0 4 H 2 0 , 1 . 5 4 ; NaHCOs, 24.9; Glucose, 5; 95% O z ; 5% C 0 2 ; p H 7.4; 37°C; 10 ml/min) and preloaded with 50 mN. After 20-30 min a stable relaxation to 20-30 mN was obtained. In addition to H 2 0 2 and tetra-butylhydroperoxide (t-BHP) (0.2-20 mmol/1), the following vasoactive agents were applied: noradrenaline (10~ 6 mol/1), KC1 (40 mmol/1, with corresponding reduction of NaCl). The substances were dissolved in 100 ml of either normal Tyrode or the corresponding Ca 2 + -free solution with 4 mmol/1 EGTA, respectively. Here again, the isometric force was measured.

Results and discussion Sensitivity of contraction to noradrenaline The contraction amplitudes after application of noradrenaline were quantitatively determined and show, that at maximal stimulation (NA, 10~ 3 mol/1) the mean value of the isometric force produced by the atherosclerotic segments ist 91 ± 3 1 mN, that of the normal segments 52 ± 3 0 mN. Additionally, the relative dose-response curves reveal, that the sensitivity of the atherosclerotic segments in reacting with contraction is shifted to lower noradrenaline contractions by one order of magnitude (fig-1). Although the explanation of this finding is still in discussion — e.g. increased number of receptor molecules on the cell surface or alterations in the coupling of receptor to contractile apparatus — it demonstrates the increased readiness and force of atherosclerotic vessels to react with contraction on exogenous catecholamines. Although in man a number of factors are thought to be responsible for the induction of vasospasm, it is a fact, that atherosclerotic vessels have a tendency for sustained vasospasm, making this model suitable for studying the cause of the hypersensitivity.

Contraction induced by hydroperoxides Spasm after depletion of glucose Similar to bronchial smooth muscle [8], vascular smooth muscle is activated in the presence of hydrogen peroxide, which must be regarded as a normal metabolite of cells with an aerobic metabolism [2]. Its production can be increased under various pathophysiological conditions e.g. during autoxidation of hemoglobin, reoxygenation after ischaemia, or stimulation of granulocytes. In our investigations concentrations of H 2 0 2 and t-BHP above 0.2 mmol/1 evoked reversible contractions. Since there are potent enzyme systems in the cells detoxifying the hydroperoxides [2], their

Experimental investigations of noradrenaline- and hydroperoxine induced contractions Norepinephrine

Fig. 1

63

Dose- Response-Curve

Dose-response-curves to noradrenaline of normal - • - and atherosclerotic -o- vessel segments. The absolute values of the force under maximal stimulation (at 10" 3 mol/1 noradrenaline) are 5 2 ± 3 0 mN for the normal and 91 ± 3 1 mN for the atherosclerotic segments.

intracellular threshold for this contraction-stimulating effect may be considerably lower. The ability of vascular smooth muscle to relax following the application of hydroperoxides depended on the substrate supply of the cells. When exogenous glucose was stepwise reduced to zero, the duration of the contractions increased up to permanent contracture (spasm). Effect of reduction of extracellular Ca 2 + Figure 2 shows the result of a typical experiment in which the dependency of the peroxide-induced contraction from extracellular Ca 2 + was studied. For comparison contractions were induced by noradrenaline ( 1 0 - 6 mol/1) and KC1 (40 mmol/1), all applied in Ca 2+ -containing and Ca 2 + -free solutions. It is obvious that the KC1induced contraction is strongly dependent on extracellular Ca 2 + , whereas the development of isometric force after application of NA gradually decreases in Ca 2 + -free solution. This means that the Ca 2 + pools sensitive to NA become empty. In contrast, repeated stimulation by H2O2 evoke contractions which rather tend to increase in

H. Heinle, D. Kling and E. Betz

64

Contraction

of

Carotid

Artery.

3C

3C I

F ImN)

g 10 M NA Q 40 mM KCl ^ 2 mM HjOJ NT: Nor mal1,tyrode Courte: Co -freeEGTA-Tyrod«

30

20

0

Fig. 2

100

200

300

¿00

t(min)

2+

Influence of exogenous Ca on contraction of carotid artery. Results of a typical experiment in which an arterial segment was superfused with normal Tyrode solution (NT) or Ca 2 + -free Tyrode containing EGTA (4 mmol/1). The bars represent the maximal isometric contraction forces evoked by the indicated stimulators.

Ca 2 + -free solution. Furthermore, this type of contraction induced in normal vascular smooth muscle is not influenced by the calcium antagonist verapamil (10~ 6 mol/1). Reperfusion with Ca 2 + -containing solution normalizes the situation: KCl and H2O2 induce contractions similar to the initial ones. In the case of NA a KCl stimulation must precede in order to obtain the original contraction force. This indicates that the Ca 2 + pools sensitive to NA can only be filled after a sufficient Ca 2 + influx. Aside from still unknown actions, the finding of the peroxide-induced contraction can be explained by various, perhaps mutual supporting mechanisms. As shown in other tissues [7] hydroperoxides can release C a 2 + from intracellular stores which activates the calmodulin-dependent myosin light chain kinase. The phosphorylated form of myosin is thought to be essential for smooth muscle contractions (for rev. see e.g. [3]). Additionally, hydroperoxides may inhibit ATP-dependent C a 2 + sequestration [4]. Therefore it is conceivable that in Ca 2 + -free solution the cellular Ca 2 + -pools are not as rapidly depleted as during stimulation by NA due to inhibited C a 2 + transport systems. The degradation of hydroperoxides involves their intracellular reduction by glutathione peroxidase, thus forming oxidized glutathione and NADP. Although not known in detail, there is evidence that various protein phosphatases are inhibited under oxidizing conditions, especially in the presence of oxidized glutathione. As-

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suming that dephosphorylation of myosin by the myosin light chain phosphatase is necessary prior to relaxation, an inhibition of this enzyme would increase the amount of phosphorylated myosin and thus facilitate and/or prolong contraction. Recent studies suggest [3], that the cross bridge cycling of phosphorylated myosin with actin is independent of C a 2 + . Therefore this mechanism could be responsible for contractions maintained at very low intracellular levels of Ca 2 + . A third mechanism by which hydroperoxides might interfere with the contractile state of vascular smooth muscle is their ability to influence the biosynthesis of prost a g l a n d i n s and prostacycline [9] both which are involved in the regulation of vascular tone but their manner of action is unknown. Although this discussion of hydroperoxide-induced contraction of vascular smooth muscle lets many questions unanswered, it might shed some light on the problem of vasospasm after subarachnoid hemorrhage. If it can be confirmed that increased lipid peroxidation, e.g. induced by the autoxidation of hemoglobin, accompanies vasospasm, one has to consider such causes of spasms, which are independent from extracellular Ca 2 + and may still persist after the application of calcium blocking agents.

Summary Experimental investigations showed that rabbit's atherosclerotic vessel segments respond with increased contraction force and an increased sensitivity to exogenous noradrenaline. In man atherosclerotic vessels tend to sustain vasospasm, and these experiments offer an explanation for the occurence of this hypersensitivity. In a second series of experiments the properties of contractions induced by hydroperoxides were studied. It is apparent that this type of contraction is not directly dependent on extracellular Ca 2 + . Whether intracellular Ca 2 + stores other than the increased noradrenaline-sensitivity or whether changes in the degree of myosin phosphorylation play an important role remains to be established.

References [1] Betz, E. and W. Schlote: Responses of vessel walls to chronically applied electrical stimuli. Basic Res. Cardiol. 74, 1 0 - 2 0 (1979). [2] Chance, B., H. Sies and S. A. Boveri: Hydroperoxide metabolism in mammalian organs. Physiol. Rev. 59, 5 2 7 - 6 0 5 (1979). [3] Hartshorne, D. J.: Biochemistry of the contractile process in smooth muscle. In: L. R. Johnson (ed.), Physiology of the Gastroinestinal Tract, pp. 243-267. Ravens Press, New York 1981. [4] Jones, D. P., H. Thor, M. T. Smith, S. A. Jewell and S. Orrenius: Inhibition of ATP-dependent

66

H. Heinle, D. Kling and E. Betz microsomal C a 2 + sequestration during oxidative stress and its prevention by glutathione. J . Biol. Chem. 2 5 8 , 6 3 9 0 - 6 3 9 3 (1983).

[5] Linke, A. and E. Betz: Excitability and NADH-fluorescence of spontaneously active portal veins in relation to glucose withdrawal. Blood Vessels 16, 2 9 5 - 3 0 1 (1979). [6] Sasaki, T., S. Wakai, T. Asano, T. Watanabe, T. Kirino and K. Sano: The effect of a lipid hydroperoxide of arachidonic acid on the canine basilar artery. J . Neurosurg. 5 4 , 3 5 7 - 3 6 5 (1981). [7] Schwartz-Serensen, S., F. Christensen and T. Clausen: The relationship between the transport of glucose and cations across cell membranes in isolated tissues. X . Biochim. Biophys. Acta 6 0 2 , 4 3 3 - 4 4 5 (1980). [8] Stewart, R. M . , E. K. Weir, M . R. Montgomery and D. E. Niewoehner: Hydrogenperoxide contracts airway smooth muscle: a possible endogenous mechanism. Respir. Physiol. 4 5 , 333—342 (1981). [9] Taylor, L., M . J . Menconi and P. Polgar: The participation of hydroperoxides and oxygen radicals in the control of prostaglandin synthesis. J . Biol. Chem. 2 5 8 , 6 8 5 5 - 6 8 5 8 (1983). [10] Wiegel, W.: Aktive und passive mechanische Eigenschaften atheromatöser Proliferate der Arteria carotis bei Kaninchen. Thesis, Tübingen 1 9 8 3 .

Regulating mechanism of cerebral micro-circulation during enhanced and decreased functional activity of nervous tissue Elfriede Leniger-Follert

The concept of a metabolic regulation of cerebral blood flow which was at first hypothesized by Roy and Sherrington in 1890 [21] and has been generally accepted for the last fifteen years, especially since methods have been developed and applied for the direct measurement of regional cerebral blood flow (CBF) and local glucose utilization. Roy and Sherrington believed that CBF is locally adjusted to metabolism and functional activity. In 1977 and 1978, Sokoloff et al. [22, 23] could demonstrate that, under normal conditions, a linear relationship existed between glucose utilization and blood flow in various cerebral structures with a coefficient of correlation, r, of 0.96. This linear relationship also existed when the functional activity was changed, for example, during general anaesthesia or during enhanced activity such as seizures or visual stimulation. In these experiments, however, r was about 0.8. Whereas the coupling between blood flow and metabolism is generally accepted, controversial opinions persist regarding the mechanisms responsible for the tight coupling during changes in functional activity. Several factors such as extracellular H + activity, extracellular K + activity, adenosine concentration, tissue hypoxia, and neurogenic factors have been proposed as mediators responsible for the adjustment of CBF in response to the metabolic demand. As pointed out by Kuschinsky and Wahl [13] and Winn et al. [27], a substance which is considered as a mediator of regulation must fulfill at least two criteria: 1. it must be a potent dilator of cerebral "resistance vessels" when applied locally, and 2. its concentration in the perivascular space must change with changing activity and changing metabolism of the brain tissue. Furthermore, the time course and magnitude of the increase in the vasodilator substance must be parallel to the metabolically induced increase in CBF. Micro-application studies with artificial mock solution performed by Betz et al. [4], Betz and Czornai [3], Wahl and Kuschinsky [25], Kuschinsky and Wahl [12], Greenberg and Reivich [9], and Berne et al. [2] clearly demonstrated that the pial and also the intra-parenchymal 'resistance vessels' dilated when the perivascular H + and K + activity and the adenosine concentration were increased whereas an increase in extracellular C a + + activity constricted the vessels.

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Additionally, several transmitter substances such as histamine, serotonine, VIP (vasoactive intestinal polypeptide), and APP (avian pancreatic polypeptide) were vasoactive. Furthermore, it is known that tissue hypoxia leads always to a vasodilation of cerebral vessels with concomitant hyperaemia. A controversial discussion still persists whether the factors cited above are responsible for the regulation of cerebral blood flow under in vivo conditions when functional activity and metabolism is altered. Although numerous electrophysiological studies have clearly demonstrated that the extracellular K + activity increases during activation of the nervous tissue from the normal stable level of about 3 m M to a range in which the K + activity exerts a dilatatory action on the resistance vessels, Astrup et al. [1] drew the conclusion that K + could not be a main factor in the control of cerebral blood flow during activation and during other situations which result also in cerebral vasodilatations. Their arguments against K + as an important coupling factor were the lack of changes in extracellular K+ activity seen in their experiments during cerebral vasodilatation occurring in severe hypoglycaemia and after amphetamine administration. These authors stated also in the same article that the extracellular H + activity may be of minor importance for the regulation of the cerebral circulation. This conclusion was based on the results of measurements of the extracellular p H in the rat cortex during bicuculline induced generalized seizures and during severe hypoglycaemia. During generalized seizures, Astrup et al. [1] found in the rat cortex with the onset of seizures an initial alkalotic shift which lasted about 20 s. After 20 s, p H reversed and a progressive acidosis developed (Heuser [10] reported in 1978 that an acidotic shift occurred in the cat cortex without an initial alkalotic change about 15 to 20 s after the onset of increase in blood flow during bicuculline induced seizures). Furthermore, Astrup et al. [1] found no change in extracellular p H in the rat cortex during severe hypoglycaemia and after infusion of amphetamine. Finally, those authors argued that CBF already increased during arterial hypoxia at a time when the extracellular p H was still alkalotic. Beside H- and K ions, adenosine has been widely discussed as a regulation mechanism (for review see [27]). At first view, adenosine seems to fulfill the criteria necessary to be considered as a mediator of metabolic regulation of CBF. It is a potent dilator of cerebral "resistance vessels" in a concentration range between 10~ 7 and 10" 3 M when applied topically [2, 25]. In addition, the concentration of adenosine increases in the brain during conditions of reduced oxygen supply and during enhanced activation as well as during bicuculline induced seizures in rats and cats and during direct electrical stimulation. However, there are still some problems which have not been clarified: Firstly, as the adenosine concentration was determined for the whole tissue by biochemical methods, it remains unclear whether the measured increase in adenosine concentration is solely extracellular. The second, more important argument against

Regulating mechanism of cerebral micro-circulation

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adenosine as a regulating mechanism for CBF is the fact that adenosine, when dissolved in a more acidic or a higher potassium containing solution, has a diminished dilatory effect on pial arterioles. When the mock spinal fluid contains 10 mM K + , practically no dilating effect of adenosine in the concentration range of 10~ 7 to 1 0 " 3 M can be observed [26]. Since the brain's extracellular K + activity increases to this level (6 to 10 mM) very rapidly during strong activation, adenosine may have no great importance under these conditions. Thirdly, it is yet not possible to obtain truly continuous measurements of adenosine concentration in relation to temporal changes in CBF. It is still uncertain whether the autonomic vascular nerves play a role in regulating CBF. The application of special methods has shown that cerebral pial and intraparenchymal arteries and arterioles as well as veins are invested with a dense plexus of perivascular nerve fibers containing neurotransmitters such as noradrenaline, serotonine, histamine, vasoactive intestinal polypeptide, substance P, avian pancreatic polypeptide and acetylcholinesterase (for review see [6, 5,11]). Despite the existence of corresponding receptors in the vessels the functional significance of the innervation of cerebral vessels remains controversial. The published results of the role of tissue hypoxia as a possible trigger mechanism for flow increase during activation are controversial. Whereas some authors assume that tissue hypoxia is, at least in part, responsible for the dilatation of the vessels during seizures, other research groups come to the conclusion that neither hypoxia or anoxia occurs during enhanced functional activity ot the brain tissue. In investigations of our own we examined the problem of regulation of microflow and its regulation mechanisms in the brain. As a first step we activated the cerebral cortex of the cat by direct electrical stimulation and investigated whether the flow in the microcirculatory range ( = microflow) behaves similarly as the regional flow which is averaged over large tissue volumes. We were able to show [18] that with onset of direct electrical stimulation, microflow uniformly increased within 1 s in the activated tissue area. The maximal increase was obtained after some seconds after the end of stimulation and then microflow gradually returned to the initial level within some seconds up to some minutes. The extent of the increase and the duration of return to the pre-stimulation level was dependent on the stimulation parameters. Simultaneous polarographic P02 measurements in parallel to microflow measurements clearly showed that the increase in flow was not triggered by tissue hypoxia as local tissue P02 increased at the onset of activation in parallel to the increase in microflow without an initial P02 decrease. In a second step, together with Hossmann, we investigated the behaviour of microflow in the right somato-motor cortex of the cat during physiological specific sensory stimulation. The contra-lateral left forepaw was stimulated with electrical impulses of 0.3 ms duration. Amplitude and frequency of the applied voltage were varied.

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With the occurrence of evoked potentials, microflow increased in the s o m a t o - m o t o r cortex during stimulation of the contra-lateral forepaw. The increase in f l o w was the stronger the higher the peak-to-peak amplitude of the evoked potentials was. When the stimulation parameters were below the threshold and n o potentials occurred, no change in microflow was observed. The increase in flow was defined to a small area of about 1 to 2 m m in diameter [17]. In a third step, beside the t w o modes of local tissue activation, we examined the behaviour of microflow during generalized seizures. The seizures were induced in cats by intravenous injection of bicuculline (1.2 mg/kg body weight). W e could demonstrate that microflow normally increased within 1 to 2 s after the onset of seizures. The m a x i m u m hyperaemia coincided with the m a x i m u m in electrical activity, shown by amplitude and voltage analysis of the electrocorticogram by fast Fourier analysis. Immediately after the onset of a silent phase, microflow distinctly and continuously decreased on all sites. At the onset of new epileptic discharges, microflow again increased. Thus, microflow oscillated in parallel to the functional electrical activity. W h e n the period of rhythmical epileptic discharges and intermediate silent phases ceased, microflow continuously decreased within a few minutes to a new steady-state level which dependend on the power of the E C o G [14]. pC>2 measurements in parallel to microflow registration showed that the increase in microflow during generalized seizures was not due to tissue hypoxia. Tissue pC>2 normally increased with the onset of seizures and oscillated during the period of repetitive silent and nonsilent phases. The hyperaemia begins rapidly and is matched by increased oxygen consumption. Furthermore local oxygen partial pressures increase as well. This pC>2 increase may, in part, be due to the disproportional increase in the oxygen transport capacity of the capillary blood during hyperaemia. W h e n the capillary blood flow increases, local hematocrit is higher, as reported by Gaethgens et al. [7, 8]. As tissue hypoxia could be excluded as a trigger mechanism for hyperaemia during activation, we systematically investigated whether extracellular H + and K + activities play a role as coupling factors and examined whether adrenergic and cholinergic nerve fibers were responsible for the regulation of flow during extreme activation. O u r measurements with H + -sensitive glass microelectrodes demonstrated a biphasic behaviour of the extracellular p H during direct electrical stimulation. W i t h the onset of direct activation an alkalotic shift occurred which was followed by an acidotic shift at the earliest after 7 s. The m a x i m u m of acidosis was always observed after the end of the electrical stimulation in parallel to the m a x i m u m hyperaemia. Then p H returned, in parallel to microflow, to its pre-stimulation level. The initial alkalotic shift and the following acidotic change were the stronger the stronger the stimulation parameters [19, 24].

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During bicuculline induced seizures, the extracellular H + activity also increased with a delay of some seconds, however, in most cases without an initial alkalotic shift. The maximal acidotic change amounted to 0.3 to 0.5 pH units and occurred at the same time as maximal electrical activity. During the phase of oscillating functional activity, extracellular H + activity also oscillated. It decreased during the silent phases and increased again during the nonsilent phases. As soon as the seizures completely ceased, H + activity also decreased. In contrary to these extreme modes of tissue activation, extracellular H + activity remained absolutely constant during physiological activation [15]. From these results we conclude that the hyperaemia at the onset of activation is in no way triggered by H ions. During physiological activation, pH also seems to play no role in the further course of hyperaemia. However, during unphysiological extreme activation, H + activity is obviously involved in the maintenance of hyperaemia. In these cases the lactate production is increased although oxygen is available in excess. It is not clear why glycolysis is increased under those conditions. Beside the augmented glycolysis, oxygen consumption and CO2 production is also increased. The increased production of H ions cannot be completely buffered by intracellular buffer systems. Thus, extracellular H + activity increases also after a delay of some seconds. The initial alkalotic shift can be interpreted as a CO2 washout effect by the very rapid increase in microflow. As H ions obviously do not trigger hyperaemia, we investigated the behaviour of extracellular K + activity. Within a few milliseconds, extracellular K + activity increased with all types of activation, during physiological as well as during extreme pathophysiological activation. During direct electrical stimulation, the increase in K + activity was the stronger, the stronger the stimulation parameters. However, K + activity never exceeded 10 mM. Therefore, it was always in the range where it exerts a clear vasodilatory effect on the "resistance vessels". After the end of direct electrical stimulation, K + rapidly returned to control level with an undershoot [19, 24]. After injection of bicuculline, K + activity also increased immediately with the onset of discharges. Maximal increase in K + activity amounted to 10—12 mM. During the period of oscillating functional activity, K + activity also oscillated in parallel to the electrical activity. When the seizures ceased K + activity rapidly returned. During physiological activation, K + activity also increased, however, the increase of 0.5 to 1 mM was distinctly smaller than during extreme activation. It showed the same time relationship as the increase in microflow. From these results we conclude that extracellular K + activity is mainly involved in triggering and maintaining hyperaemia during activation, als long as the tissue activation exists. Blockade of adrenergic and cholinergic receptors of the vessels by the corresponding blocker substances yielded no change in the kinetics of hyperaemia during and after

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direct electrical stimulation. Onset and maximum of hyperaemia were independent whether the hyperaemia was produced before or after the administration of blockers. The extent of hyperaemia was also the same before and after blockade of receptors. The blockade of adrenergic and cholinergic receptors before application of bicuculline led to no change in the pattern of microflow behaviour [14]. From these results we conclude that adrenergic and cholinergic nerve fibers play no important role for the regulation of CBF during extreme activation. First results during physiological activation also speak against a role of those nerve fibers during physiological stimulation. Whereas up to now the problems of coupling of microflow and functional electrical activity have been discussed, I briefly want to consider the regulation of CBF during uncoupling of function and flow under patho-physiological conditions. Norberg and Siesjo [20] have demonstrated by means of the C14-antipyrine method that CBF in the rat cortex increases during severe hypoglycaemia. Our investigations showed that microflow increases also in the cat's brain at a mean arterial glucose concentration of 1 mM [16] and remains elevated during isoelectricity. Simultaneous measurements of extracellular K + activity and microflow showed that the increase in microflow always occurs with an increase in K + activity. During severe hypoglycaemia minor acidotic shifts are also observed. During a period of 15 min of isoelectricity, extracellular pH returns to normal values whereas K + activity remains elevated. After intravenous administration of glucose, K + activity, microflow, and tissue p02 decrease again whereas an extreme acidosis of about 6.6 to 7.0 develops in the extracellular space. Obviously, the cerebral vessels are no longer sensitive to H ions during post-hypoglycaemic recovery conditions. Although K ions are also involved in triggering and maintaining hyperaemia during severe hypoglycaemia, the mechanism for the release of K ions is different from that during tissue activation. When a deficiency of glucose is present, the brain metabolises other substrates, for example amino-acids. With the metabolism of these substrates NH3 production increases. Thus, ammonia may change the permeability of the cell membrane for ions which results in an increase in extracellular K + activity. When ammonium acetate was infused into the arteria carotis via the lingual artery (Gronczewski and Leniger-Follert, unpublished results), we found that despite a strong decrease in the electrical activity (decrease in voltage of the ECoG) microflow increased in parallel to the increase in extracellular K + activity. When the K + activity exceeded a value of 20 mM, a continuous decrease in microflow was observed. When ECoG became isoelectric, K + activity had reached values of 80 up to 100 mM. The whole brain was strongly ischaemic under these conditions and the "resistance vessels" were constricted. From the micro-application studies it is known that an extracellular K + activity above 20 mM constricts the resistance vessels.

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These new findings of a strong increased K + activity with a subsequent decrease in cerebral blood flow under in vivo conditions may also be of interest for the vasospasm occurring after subarachnoidal haemorrhage. It may be possible that, after bleeding, the erythrocytes lose K ions and that the extracellular K + activity gradually increases until it reaches a concentration range where a constrictory effect on the vessels may be expected.

References [1] Astrup, J . , D. Heuser, N. A. Lassen, B. Nilsson, K. Norberg and B. K. Siesjo: Evidence against H + and K + as main factors for the control of cerebral blood flow: a microelectrode study. In: M . J . Purves (ed.), Cerebral Vascular Smooth Muscle and its Control. Ciba Foundation Symp. 56 (new series), pp. 3 1 3 - 3 3 7 . Elsevier/Excerpta Medica, North Holland, Amsterdam-Oxford-New York 1978. [2] Berne, R. M., R. Rubio and R. R. Curnish: Release of adenosine from ischemic brain. Effect on cerebral vascular resistance and incorporation into cerebral adenine nucleotides. Cir. Res. 3 5 , 2 6 2 - 2 7 1 (1974). [3] Betz, E. and M . Czornai: Action and interaction of perivascular H + , K + and C a + + on pial arteries. Pfliigers Arch. 3 7 4 , 6 7 - 7 2 (1978). [4] Betz, E., H. G. Enzenrofi and V. Vlahov: Interaction of H + and C a + + in the regulation of pial vascular resistance. Pfliigers Arch. 3 4 3 , 7 9 - 8 8 (1973). [5] Edvinsson, L.: Vascular autonomic nerves and corresponding receptors in brain vessels. Pathol. Biol., 2 6 1 - 2 6 9 (1982). [6] Edvinsson, L. and E. T. McKenzie: Amine mechanisms in the cerebral circulation. Pharm. Rev. 2 8 , 2 7 5 - 3 4 8 (1977). [7] Gaethgens, P., A. Pries and K. H. Albrecht: Model experiments on the effect of bifurcations on capillary blood blow and oxygen transport. Pfliigers Arch. 3 8 0 , 115—120 (1979). [8] Gaethgens, P.: Distribution of flow and red cell flux in the microcirculation. Scand. J . Clin. Lab. Invest. 4 1 , Suppl. 1 5 6 , 8 3 - 8 7 (1981). [9] Greenberg, J . H. and M . Reivich: Response time of cerebral arterioles to alterations in extravascular fluid pH. Microvasc. Res. 14, 3 8 3 - 3 9 3 (1977). [10] Heuser, D.: The significance of cortical extracellular H + , K + and C a + + activities for regulation of local cerebral blood flow under conditions of enhanced neuronal activity. In: M . J . Purves (ed.), Cerebral Vascular Smooth Muscle and its Control. Ciba Found. Symp. 5 6

(new series),

pp. 3 3 9 - 3 5 3 . Elsevier/excerpta Medica, North Holland, Amsterdam-Oxford-New York 1978. [11] Kontos, H. A.: Regulation of the cerebral circulation. Ann. Rev. Physiol. 4 3 , 3 9 7 - 4 0 7 (1981). [12] Kuschinsky, W., M . Wahl, O. Bosse and K. Thurau: Perivascular potassium and pH as determinants of local pial arterial diameter in cats. Circ. Res. Vol. X X X I , 2 4 0 - 2 4 7 (1972). [13] Kuschinsky, W. and M . Wahl: Local chemical and neurogenic regulation of cerebral vascular resistance. Physiol. Rev. 5 8 , 6 5 6 - 6 8 9 (1978). [14] Leniger-Follert, E. K.: Ions as chemical mediators of the vasodilatation in the cerebral nervous system during activity. In: Parenchymal Cell Activity and Ionic Control of Microvascular Flow. Vol. 2, Reviews of Microcirculation. Eds.: H. Schmid-Schonbein, G. W . Schmid-Schonbein. Martinus Nijhoff Publishers, Hingham, USA (in print). [15] Leniger-Follert, E. and C. Danz: The role of extracellular potassium and hydrogen activities in the brain cortex for regulation of cerebral microcirculation in the cat during generalized seizures and specific sensory stimulation. In: Progress in Enzyme and Ion-Selective Electrodes, pp. 100—105. Eds.:

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E. Leninger a n d Follert D. W . Lubbers, H . Acker, R. P. Buck, G. Eisenman, M . Kessler. Springer, Berlin-Heidelberg-New Y o r k 1981.

[16] Leniger-Follert, E. a n d J. Gronczewski: Extracellular K + a n d H + activities as i m p o r t a n t factors f o r the increase in m i c r o f l o w and tissue P02 in the brain cortex of cats during severe hypoglycemia. J. Cerebr. Bl. M e t . Suppl. 3 (1), 6 6 0 - 6 6 1 (1983). [17] Leniger-Follert, E. and K. A. H o s s m a n n : Simultaneous measurements of m i c r o f l o w a n d evoked potentials in the s o m a t o m o t o r cortex of the cat brain d u r i n g specific sensory activation. Pfliigers Arch. 3 8 0 , 8 5 - 8 9 (1979). [18] Leniger-Follert, E. and D . W . Lubbers: Behavior of m i c r o f l o w and local pC>2 of the brain cortex d u r i n g a n d after direct electrical stimulation. Pfliigers Arch. 3 6 6 , 3 9 - 4 4 (1976). [19] Leniger-Follert, E., R. Urbanics a n d D . W . Lubbers: Behavior of extracellular H + a n d K + activities d u r i n g f u n c t i o n a l h y p e r a e m i a of microcirculation in the brain cortex. In: Cerebrospinal Microcirculation, Vol. 2 0 , Adv. N e u r o l . , pp. 9 7 - 1 0 1 . Eds.: J. C e r v ó s - N a v a r r o , E. Betz. Raven Press, N e w Y o r k 1978. [20] N o r b e r g , K. a n d B. K. Siesjò: Oxidative metabolism in the cerebral cortex of the r a t in severe insulin-induced hypoglycemia. J. N e u r o c h e m 2 6 , 3 4 5 - 3 5 2 (1976). [21] Roy, C. S. a n d C. S. Sherrington: O n the regulation of the blood supply of the b r a i n . J. Physiol. (Lond.) 11, 8 5 - 1 0 8 (1890). [22] Sokoloff, L.: Relation between physiological f u n c t i o n a n d energy metabolism in the central n e r v o u s system. J. N e u r o c h e m . 2 9 , 1 3 - 2 6 (1977). [23] Sokoloff, L.: Local cerebral energy metabolism: its relationship to local functional activity a n d b l o o d flow. In: Cerebral Vascular S m o o t h Muscle a n d its C o n t r o l . Ciba F o u n d . Symp. 5 6 (new series), p p . 171—197. Ed.: M . J , Purves. Elsevier/Excerpta M e d i c a , N o r t h H o l l a n d , A m s t e r d a m - O x f o r d N e w Y o r k 1978. [24] Urbanics, R., E. Leniger-Follert a n d D . W . Lubbers: T i m e course of changes of extracellular H + a n d K + activities during a n d after direct electrical stimulation of the brain cortex. Pfliigers Arch. 3 7 8 , 4 7 - 5 3 (1978). [25] W a h l , M . a n d W . Kuschinsky: T h e dilatatory action of adenosine o n piai arteries of cats a n d its inhibition by theophylline. Pflugers Arch. 3 6 2 , 5 5 - 5 9 (1976). [26] W a h l , M . and W . Kuschinsky: Influence of H + and K + o n adenosine induced dilatation at piai arteries of cats. Blood vessel 14, 2 8 5 - 2 9 3 (1977). [27] W i n n , H . R., G. R. R u b i o a n d R. M . Berne: T h e role of adenosine in the regulation of cerebral b l o o d flow. J. Cereb. Blood Flow M e t a b . 1, 2 3 9 - 2 4 4 (1981).

Post-ischaemic reactivity of pial arteries, an experimental study C. Haller, W. Kuschinsky

Introduction It is well known that the regulation of cerebral blood flow is impaired after ischaemia. From observations of post-ischaemic CO2 reactivity and tests of autoregulatory capacity a concept of postischaemic vaso-paralysis has been proposed [ 1 3 , 1 4 , 16]. The existence of vaso-paralysis would imply a failure of cerebral resistance in vessels controlled by factors normally matching blood flow in response to the metabolic demands of brain tissue. During the last years it has become increasingly clear, that several local metabolic factors must play a major role in controlling cerebral blood flow [9], T w o of these factors, K + and H + , were selected for the present study investigating the postischaemic responses of pial arteries. For this study a microapplication technique was chosen. This approach offers the possibility to quantify the reactions of individual pial arteries to local changes in their perivascular environment, both under control conditions and after an ischaemic insult. Furthermore, each vessel can serve as its own control. The ischaemia was induced by intracarotid air injection, according to the model described by Fritz and Hossmann [3], who used this model extensively for investigating cerebral blood flow, electroencephalography, and the cerebral metabolic rate of oxygen. According to their findings an ischaemic insult affects that portion of the cerebral arteries which is located proximally to the capillaries and distally to the large segments. It is transient and has been observed in man as a hazard of deep sea diving [8] complicating a number of diagnostic and therapeutic procedures [6, 12].

Methods 21 adult cats of either sex were anesthetized with glucochloralose (40—50 mg/kg body weight) and artificially ventilated after inducing muscular paralysis by intravenous administration of gallamine (15 mg/kg-hour). A catheter was inserted into a femoral artery for continuous monitoring of the arterial blood pressure; through a

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catheter in the adjacent femoral vein Tyrode's solution was infused at a rate of 2.5 ml/kg- hour. Body temperature was monitored and maintained between 3 7 and 38 °C using a heating pad placed under the animal. The endtidal CO2 concentration was continuously measured by means of an infrared gas analyzer and kept within physiological range by adjusting the ventilatory parameters accordingly. In addition, arterial acidbase status was measured with an Astrup equipment. The brain surface was exposed in the temporo-parietal region and immediately covered with warm paraffin oil. Microapplication of artificial cerebrospinal fluids into the perivascular space of single piai arteries was performed by using micropipettes with sharpened tips (8—10 ^m) according to the technique described by Wahl et al. [18], The artificial cerebrospinal fluids had the following compositions: a) K + -experiments: N a + 1 5 9 , 1 5 6 , 153 or 1 4 9 m M corresponding to ^ - c o n c e n trations of 0, 3, 6 or 10 m M , C a + + 1.5 m M , H C C T 3 11 m M , Cl~ 1 5 1 m M . b) pH-Experiments: N a + 1 5 6 m M , K + 3 m M , C a + + 1.5 m M , H C 0 3 ~ 0, 5, 11 or 3 0 m M with corresponding CI "-concentrations of 1 6 2 , 157, 151 or 1 3 2 m M . All injection fluids were bubbled with 9 5 % O2 and 5 % CO2 (equilibrated with water). Their osmolarity was 3 0 4 mosmol/1. On each brain surface 3 or 4 piai arteries were chosen for the local microapplication of the artificial cerebrospinal fluids with increasing K + - or decreasing HCO3 "-concentrations, respectively. Microphotographs of individual piai arteries were taken under control conditions and 2 0 and 4 0 seconds after commencement of the perivascular microapplication. The air embolism was introduced by injection of 0 . 6 ml of blood foam into the innominate artery via a catheter introduced through the right axillary artery; the correct position of the catheter tip at the junction of the right subclavian artery and the innominate artery was verified after each experiment by thoracotomy. After the reperfusion of all vessels had been completed the microapplications were continued by injecting the test solutions at identical sites in the same order as before air embolism. Vascular diameter was measured on the microphotographs.

Results The arterial blood pressure was 131 ± 17 mmHg (x ± S E M , n = 2 1 ) ; there were no changes attributable to air embolism. In the control phase before air embolism the arterial acid-base status was: pH 7 . 3 4 ± 0 . 0 4 , pCC>2 3 1 . 7 ± 2.5 mmHg and pC>2 132 ± 8.8 mmHg (x ± S E M , n = 15). The postembolic acid-base status also was within physiological limits: pH 7 . 3 3 ± 0 . 0 4 , p C 0 2 3 0 . 7 ± 3 . 0 mmHg, PO2 1 3 2 . 5 ± 8.2 mmHg (x ± S E M , n = 15). The left side of figure 1 shows the changes of piai arterial diameter, expressed as percentage of control diameter, when varying the perivascular K + -concentration

Postischaemic reactivity of pial arteries, an experimental study

AIR EMBOLISM

77

MANNITOL

K* CONCENTRATION [rnM] OF INJECTION FLUID

Fig. 1

Concentration response curves for K + . Left side: control curve (solid line) and curve taken after air embolism (broken line). Right side: control curve (solid line) and curve seen with hyperosmolar artificial cerebro-spinal fluids (broken line). Means ± SEM. n = number of vessels tested.

before and after air embolism. The concentration-response curve during the control phase shows the well established direct linear relationship between the pial arterial diameter and the perivascular K + -concentration in the range between 0 and 10 mM. After air embolism the slope of the concentration-response curve for K + is significantly (p < 0.01) reduced. In figure 2 the analogous pre- and post-ischaemic concentration-response curves to changes in the perivascular p H are depicted on the left side: an alkalosis of the perivascular environment leads to vasoconstriction, whereas an acidosis induces vasodilatation. The slope of the postembolic pH-concentration-response curve is also significantly (p < 0.01) reduced. Since the slope of this curve is — in contrast to all other slopes presented in this paper - not significantly different from 0, it can be concluded that the vasoreactivity of the pial arteries to changes in their perivascular p H is abolished after air embolism.

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pH OF INJECTION FLUID Fig. 2

Concentration response curves for H + . Left side: control curve (solid line) and curve taken after air embolism (broken line). Right side: control curve (solid line) and curve taken with hyperosmolar artificial cerebro-spinal fluids (broken line). Means ± SEM. n = number of vessels tested.

Air embolism as such induced a marked dilatation of pial arteries, making it necessary to test, whether the postembolic concentration-response curves were obtained from dilated vessels, already in a state of decreased vasoreactivity caused by air embolism. In order to test this, the same procedure as in the air embolism experiments was employed, but instead of inducing air embolism, mannitol, in a hyperosmolar concentration (in the K + -test solutions 376 mosmol/1 and in the pH-test solutions 379 mosmol/1), was added to the injection fluids to achieve a similar degree of vasodilatation. The paired concentration-response curves on the right side of figures 1 and 2 show the relationship between pial arterial diameter and perivascular concentrations of K + or H + before and after the addition of mannitol to the microapplication fluids. When testing the vaso-reactivity to K + , there was no signifi-

Postischaemic reactivity of pial arteries, an experimental study

79

cant difference between the slope of the control and hyperosmolar concentrationresponse curve, albeit the hyperosmolar curve was shifted to more dilated values. In the corresponding pH-experiments the concentration-response curve obtained with hyperosmolar injection fluids was not only shifted into a more dilated range, but also showed a significant (p < 0.01) reduction of vaso-reactivity, yet to a lesser degree than after air embolism.

Discussion It is known that ischaemia leads to an accumulation of K + and adenosine in the brain tissue [1, 7,15]. A decreased cortical tissue pH has been measured after air embolism by Fritz and Hossman [3]. These three factors can induce a vasodilatation of cerebral vessels. Any change in the concentration of one or several of these factors and possibly other, yet unknown factors, could alter the functional integrity of the vascular smooth muscle cells. Interactions between the vasoactive effects of K + , H + and adenosine have been demonstrated [2, 11, 17]. In addition, the vasodilatation induced by these factors and possibly other mechanisms might in itself cause an impairment of the vascular reactivity by stretching of the vascular smooth muscle fibers leading to an unfavorable degree of overlap between the myofibrils. Another possibility explaining the attenuated vascular responses after ischaemia is a reduction of cerebral metabolism. Some authors [4, 5]. have demonstrated that a reduction of cerebral metabolism is associated with a decreased vascular reactivity to CO2. The mode by which the degree of cerebral metabolism could determine the quantity of vascular responses is still unknown. However, a metabolic factor seems not to be involved in the postischaemic hyporeactivity found in the present experiments for two reasons: 1. only a transient, insignificant decrease in cerebral metabolic rate of oxygen has been measured in the early post-ischaemic period [3]. 2. a reduction of cerebral metabolism by pharmacological means (gamma-hydroxybutyrate) does not impair the pial arterial reactivity to changes in perivascular pH; in fact it increases vascular reactivity (Haller and Kuschinsky, unpublished results). The major finding of the present study is the evidence for a differential influence of ischaemia on the reactivity of cerebral vessels. This graded impairment of sensitivity favours the view that these factors may act in a different way controlling cerebrovascular resistance: whereas K-ions seem to be responsible for the immediate adjustment of cerebro-vascular resistance to changes in neuronal activity, H-ions are more likely to be involved in the less acute, metabolically determined regulation of local cerebral perfusion [9].

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References [1] Berne, R. M., R. Rubio and R. R. Curnish: Release of adenosine from ischaemic brain. Effect on cerebral vascular resistance and incorporation into cerebral adenine nucleotides. Circ. Res. 35, 2 6 2 - 2 7 1 (1974). [2] Betz, E.: Ionic interaction in pial vascular smooth muscles. In: Ed. E. Betz, Ionic actions on vascular smooth muscle, p. 75—77. Springer, Berlin 1976. [3] Fritz, H. and K. A. Hossmann: Arterial air embolism in the cat brain. Stroke 10, 5 8 1 - 5 8 9 (1979). [4] Fujishima, M., P. Scheinberg, R. Busto and O. M . Reinmuth: The relation between cerebral oxygen consumption and cerebral vascular reactivity to carbon dioxide. Stroke 2, 2 5 2 - 2 5 7 (1971). [5] Grubb, R. L., M . E. Raichle, J. O. Eichling and M . M. Ter-Pogossian: The effects of changes in PaCC>2 on cerebral blood volume, blood flow and vascular mean transit time. Stroke 5, 6 3 0 - 6 3 9 (1974). [6] Horwitz, N. H. and H. V. Rizzolo: Postoperative complications in neurosurgical practice: recognition, prevention and management, p. 332. Williams &C Wilkins, Baltimore 1967. [7] Hossmann, K. A., S. Sakaki and V. Zimmermann: Cation activities in reversible ischaemia of the cat brain. Stroke 8, 7 7 - 8 1 (1977). [8] Ingvar, D. H., J. Adolfson and C. Lindemark: Cerebral air embolism during training of submarine personnel in free Europe: an electroencephalographic study. Aerosp. Med. 44, 628 (1973). [9] Kuschinsky, W.: Coupling between functional activity metabolism and blood flow in the brain: State of the art. Microcirculation 2, 3 5 7 - 3 7 8 (1982/83). [10] Kuschinsky, W. and M. Wahl: Local chemical and neurogenic regulation of cerebral vascular resistance. Physiol. Rev. 58, 656 (1978). [11] Kuschinsky, W., M. Wahl, O. Bosse and K. Thurau: Perivascular potassium and p H as determinants of local pial arterial diameter in cats. Circ. Res. 31, 240—247 (1972). [12] Menkin, M . and R. J. Schwartzman: Cerebral air embolism. Report of five cases and review of the literature. Arch. Neurol. 34, 168 (1977). [13] Paulson, O. B.: Regional cerebral blood flow in apoplexy due to occlusion of the middle cerebral artery. Neurology 20, 63 (1970). [14] Symon, L., N. M . Branston and A.J. Strong: Autoregulation in acute focal ischaemia. An experimental study. Stroke 7, 5 4 7 - 5 5 4 (1976). [15] Symon, L., N. M. Branston and A. J. Strong: Extracellular potassium activity, evoked potential and rCBF during experimental cerebral ischaemia in the baboon (abstract). Acta neurol. Scand. Suppl. 64, Vol. 56, p. 110 (1977). [16] Symon, L., H. A. Crockard, N. W. C. Dorsch, N. M. Branston and J. Juhasz: Local cerebral blood flow and vascular reactivity in a chronic stable stroke in baboons. Stroke 6, 482—492 (1975). [17] Wahl, M. and W. Kuschinsky: Influence of H + and K + on adenosine-induced dilatation of pial arteries of cats. Blood Vessels 14, 2 8 5 - 2 9 3 (1977). [18] Wahl, M., W. Kuschinsky, O. Bosse, J. Olesen, N. A. Lassen, D. H. Ingvar, J. Michaelis and K. Thurau: Effect of 1-norepinephrine on the diameter of pial arterioles and arteries in the cat. Circ. Res. 31, 2 4 8 - 2 5 6 (1972).

Comparative morphological, biochemical and pharmacological investigations of a spontaneously active smooth muscle D. Voth, M. Henn, J. Frisch

Introduction Neurosurgeons confronted with the problems of cerebrovascular spasms following subarachnoidal haemorrhage have been forced to focus their experimental work on the behaviour of vascular muscle subjected to a number of pharmacological conditions. For the last 15 years the present authors have studied the biochemical reactions of the spontaneously active portal vein of rat, rabbit and guinea pig [33, 37, 38, 39]. This early work was supported by the Deutsche Forschungsgemeinschaft (VO 96/2—6) and has been followed up and incorporated cerebral vascular investigations [14, 22]. We have chosen the portal vein for our experiments and compared these results, with those found for the inferior vena cava and believe that both veins are most suitable experimental models. The aim of these investigations has been the analysis of the events leading to contraction or dilatation and which substances affect these changes.

Material and methods The portal vein of rat, guinea pig and rabbit were used, which show rhythmic contractions under isometric conditions [23, 24, 27, 28, 31]. The histology was studied in paraffin sections using a battery of stains and electronmicroscopy was carried out after glutar-aldehyde fixation, contrasting with osmium-tetroxyde. The force of contraction was measured isometrically (c.f. Voth et al. 1977, 1981), while oxygen consumption and substrate utilisation was measured, following the Warburg method (for details see [40]). The estimation of deoxyribonucleic acid (DNA) was made, according to Webb and Levy (1955), energy-rich phosphates were determined enzymatically (c.f. [40]). This reference is also a source for methods for calculating intracellular cation-concentrations, measuring extracellular space and

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the amount of hydroxyproline for determination of collagen. The binding capacity for the octapeptid angiotensin II was measured with a substance labeled by 14 C, for its precursor Angiotensin I with a substance labeled by 3 H. Both preparations show a highly specific activity. The bound radioactivity of the vascular muscle was measured after the incubation of preparations of rabbit's portal vein in Tyrode's solution for 3 min. containing one of the labeled peptides and having passed through a tissue solubiliser. In this way it was possible measuring total radioactivity in a liquid scintillation counter, taken the quenching effect into account. After subtracting the activity attributable to ECR from the total radioactivity measuring the quantity of "bound" angiotensin I and II in ng/g wet weight was possible. Preparations from tissue of the inferior vena cava, diaphragm and abdominal aorta served as control. These preparations were incubated for 5 min. at 35 °C washed and transfered into inactive Tyrode's solution and the time course of release followed. At definite intervals the preparations were taken out to measure their activity (Methods: Voth et al. [41], Voth [42]).

Results Previous morphological studies revealed that the portal vein of the species examined contains a thick layer of muscle fibres incorporated in the adventitia. This muscle layer runs in parallel with the course of the vessel, a further muscle coat is situated in the media but courses spirally (fig. 1). When compared with the inferior vena cava the portal vein contains fewer collagenous and elastic fibres but the percentage of smooth muscle is higher. The portal vein has a hydroxy-proline content of 25.4 ± 2.4 ng/100 mg dry weight while the i.v.c. contains 59.3 ± 3.9 ng/100 mg. Furthermore electron microscopical picture reveal a higher number of mitochondria in the auto-rhythmical muscle cells of the portal vein (fig. 2), closely interdigitating cell membranes and numerous pinocytotic vesicles [33]. This appearance is valid for all preparations of smooth muscle posessing spontaneous activity. Under isometric conditions the portal vein of the above species exhibits rhythmic activity of regular contractions (fig. 3) while the i.v.c. does not respond in this manner. When examining the ionic fluxes it can be shown that K + and Ca 2 + withdrawl causes a cessation of activity similar to the replacement of Na + by Li + . An increase of Na + concentration keeping a normal or elevated Ca 2+ -concentration, causes an increase in contractility. At ph 7.6 (Alkalosis) contractility increases and decreases at pH 7.1 (Acidosis). Ca 2 + concentration increase causes a significant decrease in frequency (for further details consult Voth et al. [37]).

Fig. 1

Portal vein and inferior vena cava seen under light microscopy. a) T h e portal vein of rat shows a sizeable muscle layer in its adventitia, running parallel to the course of the vessel, the media contains spirally arranged muscle fibres. Longitudinal section, stained with Azan, x 1 2 0 . b) Tangential section of the portal vein of rat passing through both muscle layers at right angle to each other. T o the left of the picture circularly running bundles of the media can be seen, Azan,

X120. c) The differences in structure can be seen clearly in preparation stained with Van Gieson. T o the left the portal vein, on the right the i.v.c. recognizable by the richness of collagenous fibres, X420. d) A stain for elastic fibres reveals the distinctly difference of texture. The portal vein on the left contains in contrast to the i.v.c. seen on the right few elastic fibres, X 4 2 0 .

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"/• der Gesamtzellfläche

3 0 -

(XiSX)

• V. portae

2 0 -

Histogramm des relativen Flächenanteils der Mitochondrien

PataaiumVene

PatagiumArterle

10

V. cava

Mesenteriales Lymphgefäß

Mesenteriale Vene

Rattus Fig. 2

Pteropus

.avia

Histogram of relative areas of mitochondrial density in 3 spontaneously active vessels (portal vein, patagium vein of bat (Pteropus) and mesenteric lymphatics of guinea pig). These vessels are compared with non-spontaneously active vessels. Note that the mitochondrial density in autorhythmic vessels is significantly higher. (After R. Schipp. D. Voth, I. Schipp [33]).

Comparing the biochemical results obtained for portal vein and i.v.c. of rabbit it can be shown that a vessel capable of auto-rhythm like the portal vein has a lower content of intra-cellular N a + - and a higher one of K + . The concentration of C a 2 + was higher both in the tissue as a whole and intra-cellularly than in the i.v.c. [40]. Marked differences were also observed in the amount of energy-rich phosphates and the other substances examined (fig. 4). The DNA content, serving as a parameter of cell density is 1.3 times higher in the portal vein than in the i.v.c. (portal vein = 350.9 ± 16.4 mg/100 mg wet weight, i.v.c. = 268.1 ± 22.1 mg/100 mg wet weight). The degree of oxygen consumption and substrat utilization can be illustrated by the glucose consumption (fig. 5). The R Q of the portal vein is about 4 times higher than the i.v.c. consumption. Succinate is equally well metabolised but fructose only by the portal vein and hardly by the i.v.c. Pyruvate and lactate were not measurabely oxydised by the portal vein, while the low R Q of the i.v.c. corresponds to the one found for glucose. The pharmacological analysis of the auto-rhythmical vascular muscle concentrated on the effects of adrenergic substances. Blockading a- and ^-adrenergic receptors by using phenoxybenzamine and propranolol (5 X 10~ 6 gml) reveal the stimulating

85

Comparative morphological, biochemical and pharmalogical investigations

Vena cava caudalis mg

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The portal vein of rabbit, rat and guinea pig exhibit under isometric conditions a spontaneous activity in contrast to the behaviour of the i.v.c. of the same species (from D. Voth and D. Lell [40]).

p m o l / g FG 3,0 H

Eneraiereiche Phosphate in vitro (1 h Inkubation in Tyrodelösung)

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Vasospasm in hypertensive rats induced by dihydralazin (Nepresol®)

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one case this change stayed on without regressing within 15 min (fig. 3 c). In a further instance a contracture arose after repeated short phases (fig. 3 d). A high correlation was found between blood volume and pial arterial diameters [5].

Discussion Dihydralazine dilates the cerebral resistance vessels to a larger extent than could be expected from a response of the autoregulation to lowering of blood pressure [5]. Sympathetic blockade and high doses of dihydralazine dilate resistance vessels of

100

200

2mgkg 1 DIHYDR.

2mgkg 1 DIHYDR.

SHR1

100 10

1min. ~ Fig. 3 a - d

d)

M A P = mean arterial pressure in m m H g , 0 A = continuous registration of caliber changes of a pial artery in um, 0 V = pial vein in |xm, ICP = intracranial pressure in m m H g , BV = semi-quantitative photometric registration of cerebral blood v-lume (C = reduction of blood volume, D = increase of blood volume). A decrease of blood volume precedes arterial spasm.

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hypertensive animals relatively more, but the absolute diameters are still smaller than in normotensive animals due to the increased sympathetic tone and structural changes of the vascular wall of SHR. This structural limitation of arterial dilatation demands caution in anti-hypertensive therapy, especially in controlled hypotension. An awarness of acute blood flow reduction due to ascending arterial spasm caused by autohypertensive drugs has been so far not been advanced nor has the particular compound examined by us been suspected of this effect. The time difference between blood volume reduction and the constriction of small and large piai arteries favours the origin and location of this reaction to be the capillary bed, progressing towards the larger arteries. In support of this view are experimental observations using dihydralazine and diazoxide [6, 7] proving the occurrence of ischaemic lesions after anti-hypertensive drug application. Such observations could possibly explain the clinical deterioration of patients under anti-hypertensive therapy. Although results of animal experiments may not unrestrictedly be applied to man, an increased tendency for the occurrence of vasospasm has to be viewed with caution especially in patients suffering from SAH from a cerebral aneurysm.

References [1] Auer, L. M . : The pathogenesis of hypertensive encephalopathy. Acta Neurochir. Suppl. 2 7 , 1 - 1 1 1 (1978). [2] Auer, L. M.: A method for continuous monitoring of piai vessel diameter changes and its value for dynamic studies of the regulation of cerebral circulation. A preliminary report. Pfliigers Arch. 3 7 3 , 1 9 5 - 1 9 8 (1978). [3] Auer, L. M . and F. Haydn: Multichannel videoangiometry for continuous measurement of piai micro vessels. Acta Neurol. Scand. 6 0 , Suppl. 72, 2 0 8 - 2 0 9 (1979). [4] Auer, L. M . and B. Gallhofer: Rhythmic activity of cat piai vessels in vivo. Eur. Neurol. 2 0 , 4 4 8 - 4 6 8 (1981). [5] Auer, L. M . , I. Sayama and B. B. Johansson: Cerebrovascular effects of dihydralazine in hypertensive and normotensive rats. Acta Medica Scand., Suppl. 6 7 8 , 7 3 - 8 1 (1983). [6] Barry, D. I., S. Strandgaard, D. I. Graham, O. Braendstrup, U. G. Svendsen and T. B. Bolwig: Effect of diazoxide-induced hypotension on cerebral blood flow in hypertensive rats. J . Clin. Invest. 13, 2 0 1 - 2 0 7 (1983). [7] Barry, D. I., S. Strandgaard, D. I. Graham, U. G. Svendsen, O. Braendstrup and O. B. Paulson: Cerebral blood flow during dihydralazine-induced hypotension in hypertensive rats. Stroke, in Druck 1984. [8] Okamoto, K. and K. Aoki: Development of a strain of spontaneously hypertensive rats. Jap. Circ. J . 2 7 , 2 8 2 - 2 9 3 (1963). [9] Overgaard, J . and E. Skinhej: A paradoxical cerebral hemodynamic effect of hydralazine. Stroke 6, 4 0 2 - 4 0 4 (1975).

Determination of local metabolic rate and local blood flow in the brain using the 2-deoxyg}ucose- and iodoantipyrine techniques"' W. Kuschinsky

Introduction It is now possible to quantify the relationship between local metabolic rate and microcirculation in the brain. The prerequisite for such a quantification is the availability of methods, which allow a reliable measurement of both of these parameters, preferably in the conscious animal. It is desirable that these methods should be applicable to man after suitable modification, and it is hoped, that this paper presents an experimental contribution towards this aim.

Global blood flow The basis for quantitative measurement of cerebral blood flow originates from Kety's applications of Ficks's principle for measuring cerebral blood flow, as documented by C. F. Schmidt [15]. This principle "postulates in its simplest form that the quantity of any substance taken up in a given time by an organ from the blood which perfuses it, is equal to the total amount of the substance carried to the organ by the arterial inflow less the amount removed by the venous drainage during the same period" [5]. The nitrous oxide method developed on this basis [5] became the classical method to measure cerebral blood flow in experimental animals and man. This method allows the quantification of the global cerebral blood flow, when the time course of the arterial and cerebral venous concentration of nitrous oxide are known. The other parameter necessary for a quantification is the tissue concentration of the indicator substance. This cannot be determined directly, but is calculated from the cerebral venous concentration by multiplying the cerebral venous concentration of nitrous oxide with the partition coefficient for nitrous oxide between brain and blood, under the assumption of equilibrium between brain and cerebro-venous blood in relations to nitrous oxide tension.

* This investigation was supported by the Deutsche Forschungsgemeinschaft.

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Local blood flow, inert gases Application of these new methods for the measurement of global blood flow in man revealed results, which cause as a surprise to the investigators in Kety's lab: when subjecting the subjects to a state which they considered to be maximal activation (mental arithmetics) or inactivation (sleep) they found only small or no changes in global brain blood flow [10, 19]. Therefore, they soon tried to apply the same principles of measurement to the development of a method which allows one to measure local cerebral blood flow in the brain. It became apparent that local concentrations of the indicator gas could be detected in the brain, when radioactive gases were used as indicators and autoradiographic methods were applied after cryosectioning of the brain. Determination of local tissue concentrations from the optical densities in the autoradiographs had also the advantage that sampling of venous blood from the brain could be avoided since the tissue concentration, as described above, can be calculated from the venous concentration multiplied with the partition coefficient of the tracer between brain and blood. The autoradiographic method was introduced by Landau et al. [9] and its theoretical basis was described by Freygang and Sokoloff [3]. The advantages of this method however had to accept some disadvantage: since each set of measurements requires a sacrifice of the animal, repeated determinations of local blood flow in the same brain of one particular animal were impossible, and obviously the method cannot be applied in man.

Local blood flow, non-volatile tracers The method of Landau et al. [9] and Freygang and Sokoloff [3] could have opened up a new era for measuring cerebral blood flow, because of its theoretical soundness in the presentation of values of local blood flow in each portions of the brain of the awake animal. However, this kind of study using an inert radioactive gas indicator has never been repeated, either in the laboratory of origin or elsewhere. This is due to the technical disadvantages of using a radioactive inert gas like (131 J) CF3J. This gas is not available commercially, it is rather difficult to synthesize and to purify, and the processing of the tissue has to be carried out with extreme care to avoid a loss of the highly volatile tracer. It was attempted to circumvent these difficulties by using non-volatile radioactive tracers. A substance, possessing a number of advantages, when compared to (131 J) CF3J, was (14 C)-antipyrine. Furthermore the processing of the brain sections was easier, it yields a better autoradiographic resolution and, because of the long half-life of (14 c), permanent radioactive standards can be made [13]. It was later recognized by Eckman et al. [1] that the application of (14 C)-antipyrine causes a serious problem. These authors demonstrated in simulation studies and by direct measurements

Determination of local metabolic rate and local blood flow in the brain

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of cerebral blood flow in cats using (14 C)-antipyrine, that the brain tissue is apparently not in diffusion equilibrium with the venous blood. This was in agreement with an earlier study of Eklof et al. [2]. The uptake of (14 C)-antipyrine by the brain tissue is not entirely flow limited, although this is essential for a blood flow marker, but it is partly also permeability limited. Therefore Sakurada et al. [14] have introduced (14 C)-iodoantipyrine as a blood flow marker. This substance is accepted as the best available indicator for the measurement of local cerebral blood flow by tissue sampling (e.g. [11]). For this reason this indicator was also chosen in the present study for the quantifaction of the relationship between local cerebral glucose utilization and local cerebral blood flow. Local cerebral blood flow was determined in the awake rat by using the method, described by Sakurada et al. [14]. The only methodological difference was that, in the present study, (14 C)-iodoantipyrine was infused with increasing speed during the 60 seconds'-measuring period, to ensure a high arterio-venous difference for the marker over the whole measuring period.

Quantification of the metabolic rate in individual brain areas The idea to use a quantitative autoradiographic technique for measuring local metabolic rates in the brain tissue was difficult to achieve. The normal substrates of cerebral energy metabolism are oxygen and glucose. Both these substrates are so rapidly converted to CO2 in the brain, that a quantitative trapping of only one of them for autoradiographic purposes is impossible. Sokoloff has recently introduced a method which uses a labeled analogue of glucose, 2-deoxy-D-( 14 C) glucose, (( 1 4 C)DG) [20], ( 1 4 C)DG is metabolized through the main pathway of glucose metabolism. The product of phosphorylation, however, ( 14 C)DG-6-phosphate, is trapped in the tissue, necessary for the application of the quantitative autoradiographic technique. In order to achieve a state, in which the concentration of radioactivity in the tissue could be correlated to the rate of glucose utilization, Sokoloff has developed a model, which is based on the biochemical properties of deoxyglucose and glucose [17, 20]. The model takes advantage of the fact that deoxyglucose and glucose are competitive substrates for both blood-brain transport and hexokinasecatalyzed phosphorylation. The quantity of ( 14 C)DG-6-phosphate accumulated in the tissue at any time after introduction of ( 1 4 C)DG into the circulation is equal to the integral of the rate of ( 1 4 C)DG phosphorylation by hexokinase during that interval of time. This integral is related to the amount of glucose that has been phosphorylated over the same interval, and this relationship can be quantified and expressed as glucose utilization of the brain tissue.

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W. Kuschinsky

Correlation between local cerebral glucose utilization and local cerebral blood flow The availability of methods which allow the quantification of local glucose utilization and local blood flow in individual brain areas permits definition of the quantitative relationship between these parameters. Due to the wide variability of measured values of both local cerebral blood flow and local cerebral glucose utilization, it was of interest to investigate this relationship in normal and alert rats. In one experimental group of rats, local glucose utilization was measured in 39 areas of gray and white matter, and in the other group local blood flow was determined for the same areas. The results are shown in figure 1. The excellent correlation between local cerebral glucose utilization and local cerebral blood flow is apparent. These data can be taken as evidence for a coupling between local metabolism and local blood flow in the brain, which takes place on a long-term basis. The date are in accordance with a study of the relationship between local metabolic rate for oxygen and local blood flow in the brain cortex of man [12]. These authors found a correlation between the local metabolic rate of oxygen and local blood flow. It would be of interest to compare the values found for local glucose utilization and local blood flow with the values determined for global metabolism and blood flow in many earlier studies. An additional measurement of global glucose utilization and blood flow became possible by the aid of computerassisted densitometry [4]. The films with the autoradiograms were scanned, and the optical densities of all sections were measured. These values were then converted to either blood flows or glucose utilizations. The average of all these values allows one to compare the results of the autoradiographic studies with the results of other studies, in which global methods had been employed, whereas taking just the average of the 39 measurements could give a different value, since it would only average the values of some selected picture. The average in this study, obtained by scanning the whole films, was for glucose utilization 86.6 |a, moles/100 g-min and for blood flow 106.7 ml/100 g-min. These values are in a range to be expected for the awake rat brain from other, global methods [16]. The question then arose, whether this close relationship between local glucose utilization and local blood flow, as shown in figure 1, is a fixed or variable one, when the experimental conditions were altered. A change in the systemic acid base was chosen for the experimental model, for metabolic acidosis is a rather common clinical feature and the H + concentration is one of the factors which mediate the acute adjustment of local flow to changing metabolic needs. Metabolic acidosis induced a reduction of local cerebral glucose utilization in all brain structures tested. The average glucose utilization, obtained by scanning the whole films, was reduced by 29%. In contrast to this, blood flow was only insignificantly reduced by 8%. This dissociation between decrease in glucose utilization and blood flow does not indicate a major impairment of the relationship between local glucose utilization and local blood flow. This is demonstrated in figure 2. In this figure the values for local glucose

Determination of local metabolic rate and local blood flow in the brain

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Relationship between local cerebral glucose utilization and local cerebral blood flow in 39 different anatomical brain structures of normal conscious rats. (From [7], with permission.)

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ACIDOSIS 340 LOCAL CEREBRAL 320 BLOOD FLOW 300 (ml/100g/min)

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Linear Regression Equation: Y = - 2 3 . 2 + 2.6 X Correlation Coefficient -

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Relationship between local cerebral glucose utilization and local cerebral blood flow in 39 different anatomical structures of rat brain during metabolic acidosis. (From [7], with permission.)

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C o m p a r i s o n of the relationship between local cerebral glucose utilization and local cerebral b l o o d flow during control (x) and acidosis (o). Connecting lines have been drawn between identical structures. (From [7], with permission.)

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utilization are plotted against the local blood flows of the same brain structures as in figure 1, but for the two groups of acidotic rats. It is evident that the degree of acidosis induced in these experiments did not affect the correlation between local glucose utilization and local blood flow, as indicated by the nearly unchanged correlation (0.95), compared with control conditions (0.96). On the other hand, there was a difference between both groups, as shown in figure 3. This figure show, for comparison, the regression lines of figures 1 and 2. The values for the individual structures during control conditions have been connected with the values during acidosis. Although there was excellent coupling in both conditions, the amount of change in blood flow per amount of change in glucose utilization was altered by acidosis, as indicated by the different slopes of the two regression lines. The difference between slopes was statistically significant (p < 0.01). Further experiments were performed to test the relationship between local cerebral glucose utilization and local cerebral blood flow during norepinephrine infusion [6] and during the action of gamma-hydroxybutyrate [8]. In both experiments, we found an increased steepness of the slope of the regression line. This shows that the amount of blood flow needed to perfuse a brain structure is not fixed completely to its metabolic rate, but can vary even at the same metabolic rate, dependent on the experimental conditions. This variability of local blood flow is present although a close correlation between local metabolic rate and local blood flow is still existing. If it were possible to obtain variable values for blood flow at a certain metabolic rate, a useful therapeutic tool for treating vasospasm were obtained. Apart from the current efforts to relieve the deficiency in cerebral blood flow by ameliorating the vasospasm, one should attempt establishing conditions for a low blood flow at the given metabolic rate. A therapeutical reduction of the cerebral metabolic rate would be acceptable, if a relatively low blood flow were permissible. Even at an unchanged cerebral metabolic rate it may be possible to reduce the cerebral blood flow moderately without endangering the metabolism of the tissue.

References [1] Eckman, W. W., R. D. Phair, J . D. Fenstermacher, C. S. Patlak, C. Kennedy and L. Sokoloff: Permeability limitation in estimation of local brain blood flow with ( 1 4 C)-antipyrine. A m J. Physiol. 2 2 9 , 2 1 5 - 2 2 1 (1975). [2] Eklof, B., N . A. Lassen, L. Nilsson, K. Norberg, B. K. Siesjo and P Torlof: Regional cerebral blood flow in the rat measured by the tissue sampling technique; a critical evaluation using four indicators C 1 4 -antipyrine, C 1 4 -ethanol, H 3 -water and X e n o n 133. Acta physiol. scand. 9 1 , 1 - 1 0 (1974). [3] Freygang, W. H., Jr. and L. Sokoloff: Quantitative measurement of regional circulation in the central nervous system by the use of radioactive inert gas. Adv. Biol. M e d . Physics. 6, 2 6 3 - 2 7 9 (1958).

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[4] Goochee, C., W. Rasband and L. Sokoloff: Computerized densitometry and color coding of ( 14 C)deoxyglucose autoradiographs. Ann. Neurol. 7, 359—370 (1980). [5] Kety, S. S. and C. F. Schmidt: The effects of altered arterial tensions of carbon dioxide and oxygen on cerebral blood flow and cerebral oxygen consumption of normal young men. J. Clin. Invest. 27, 4 8 4 - 4 9 2 (1948). [6] Kuschinsky, W., S. Suda, R. Biinger, S. Yaffe and L. Sokoloff: The effects of intravenous norepinephrine on the local coupling between glucose utilization and blood flow in the rat brain. Pfliigers Arch. 398, 134-138 (1983). [7] Kuschinsky, W., S. Suda and L. Sokoloff: Local cerebral glucose utilization and blood flow during metabolic acidosis. Am. J. Physiol. 241, H 7 7 2 - H 7 7 7 (1981). [8] Kuschinsky, W., S. Suda and L. Sokoloff: The relationship between local cerebral glucose utilization and local cerebral blood flow during the action of gammahydroxybutyrate. (abstract). Pfliigers Arch. Suppl. 392, R 10 (1982). [9] Landau W. M., W. H. Freygang Jr., L. P. Rowland, L. Sokoloff and S. S. Kety: The local circulation in the living brain; values in the unanesthetized and anesthetized cat. Trans. Am. Neurol. Assoc. 80, 1 2 5 - 1 2 9 (1955). [10] Mangold, R., L. Sokoloff, E. Conner, J. Kleinermann, P.-O. G. Therman and S. S. Kety: The effects of sleep and lack of sleep on the cerebral circulation and metabolism of normal young men. J. Clin. Invest. 34, 1 0 9 2 - 1 1 0 0 (1955). [11] Ohno, K., K. D. Pettigrew and S. I. Rapoport: Local cerebral blood flow in the conscious rat as measured with 14 C-antipyrine, 14 C-iodoantipyrine and 3 H-nicotine. Stroke 10, 6 2 - 6 7 (1979). [12] Raichle, M . E., R. L. Grubb, M. H. Gado, J. O. Eichling and M . M . Ter-Pogossian: Correlation between regional cerebral blood flow and oxidative metabolism. Arch. Neurol. 33, 523—526 (1976). [13] Reivich, M., J. Jehle, L. Sokoloff and S. S. Kety: Measurement of regional cerebral blood flow with antipyrine-14 C in awake cats. J. Appl. Physiol. 27, 2 9 6 - 3 0 0 (1969). [14] Sakurada, O., C. Kennedy, J. Jehle, J. D. Brown, G. L. Carbin and L. Sokoloff: Measurement of local cerebral blood flow with iodo( 14 C)antipyrine. Am. J. Physiol. 234, H 5 9 - H 6 6 (1978). [15] Schmidt, C. F.: The early days of the indifferent gas method for measuring cerebral blood flow. J. Cereb. Blood Flow Metabol. 2, 1 - 2 (1982). [16] Siesjo, B. K.: Brain energy metabolism. John Wiley and Sons, Chichester 1978. [17] Sokoloff, L.: Mapping cerebral functional activity with radioactive deoxyglucose. Trends Neurosci. 1, 7 5 - 7 9 (1978). [18] Sokoloff, L.: Localization of functional activity in the central nervous system by measurement of glucose utilization with radioactive deoxyglucose. J. Cereb. Blood Flow Metabol. 1, 7 - 3 6 (1981). [19] Sokoloff, L., R. Mangold, R. L. Wechsler, C. Kennedy and S. S. Kety: The effect of mental arithmetic on cerebral circulation and metabolism. J. Clin. Invest. 34, 1101-1108 (1955). [20] Sokoloff, L., M . Reivich, C. Kennedy, M. H. Des Rosiers, C. S. Patlak, K. D. Pettigrew, O. Sakurada and M. Shinohara: The ( 14 C)deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat. J. Neurochem. 28, 8 9 7 - 9 1 6 (1977).

Vasoconstrictor and vasodilator substances, their effect on arterial preparations under isometric and constant flow conditions M. Henn, D. Voth

Introduction For some years now we have concentrated our experimental efforts examening the reactive properties of smooth vascular muscle of veins to substances such as prostaglandin, prostacyclin, methysergide and cyproheptadine [12]. Lately we have included observations on smooth muscle of arteries [8] and present at this meeting some of our results on two of the arteries studied: The common carotid artery of the rat and the basilar artery of the rabbit [3, 7]. The third artery studied, the internal carotid artery will be reported on at a future publication.

Methods After dissecting the common carotid artery 2—2.5 mm long segments were mounted between two glass capillaries in 5 ml temperature-controlled (37 °C) tissue baths under a preload of up to 10 mN, rinsed and immersed in a Tyrode's solution bubbled with 95% O2 and 5% CO2. The ring like preparation was kept for 90 min. at 37.0 0 until the test substance was added. Measurements, carried out under "isometric" conditions, were taken with a highly sensitive Statham transducer and the signals displaye on a Hellige polygraph. In view of the small vascular lumen of the segment of the rabbit's basilary artery it was necessary to test in a "constant flow" — preparation. On one end the vascular portion was mounted over the tip of a glass capillary and perfused with Tyrode's solution bubbled with 95% O2 and 5% CO2 for 2 hrs at 37.0 The pump used was a piston pump (TEXMA) and the perfusion rate was 5 ml/min. The pressure variations were measured with a high sensitivity piezoelectric pressure transducer. The amplifier contained a low frequency filter to exclude the frequency of the pump itself.

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Results As a first vasoconstrictor substance serotonin was chosen [1, 2, 4] and methylergobasin, for vasodilator effects the calcium antagonists verapamil and D 600-HCL (Gallopamil)* [7, 11]. To start with, the dose-effect relation of serotonin and methyl-ergobasin were plotted, using increasing doses in equimolar range, for serotonin in a concentration range 2.5 X 10~ 7 — 2.5 X 10~ 5 mol/1 and for methylergobasin from 2.5 x 1 0 " 7 - 2.5 x 1 0 " 5 mol/1. It could be shown in the case of methyl-ergobasin, that a 10 times higher dose of methyl-ergobasin had to be used, to obtain a comparable and adequate contraction we had previously seen for a preparation of a definite measurable contraction at a molar range of 2.5 X 10~ 6 . When using the highest molar range within the experimental setting, both substances yielded the same vasoconstrictor effect (1.9 mN). From several experiments the conclusion was reached that the C a 2 + antagonists verapamil and D 600-HCL showed a vasodilator action only after a previous vasoconstrictor stimulus. We assume that 5-hydroxytryptamine (5-HT) must play a role in the early phase of the development of vasospasm and used serotonin as an initial vasoconstrictor stimulus. For this reason 5 HT was added to the bath in a very high concentration 2.5 X 10~ 5 mol/1, a range previously found to be effective. The degree of the resulting vasoconstriction (active tonisation) was taken as a reference point for the vasodilatory action of C a 2 + antagonists and was taken to be 100% [10]. The substances verapamil and D 600-HCL were tested in increasing concentration using comparable molar concentrations (figs. 1, 2). It was evident, that D 600-HCL at a concentration of 2.4 X 10~ J mol/1 showed already an effect, resulting in a decrease to 62.5% in relation to the reference point. Verapamil however showed no effect, its threshold was in a 10 times higher molar range. When following this up in ascending ranges of concentration it was clearly evident that D 600-HCL has a significantly higher vasodilator action than verapamil. Verapamil in the highest dose range is unable abolishing the vasoconstrictory effect of serotonin, while D 600H C L has this proparity in all nine experimental series. A vasodilation, exceeding the arbitrary value of 100%, could not be demonstrated. The next preparation examined in a constant flow preparation was the basilar artery of rabbit and serotonin was used also for achieving active tonisation. The value recorded served as previously as a reference point for judging dilator action. On * Verapamil available under the tradenames of Isoptin®, Cordilox®, Calan®, Manidon®, Dilcoran®, Vasolan®, Ikacor®. Therapeutic dose range used in cardiology: 3 X 80 mgs to 3 X 160 mgs/day, orally, 100 mgs/24 hours as infusion. Gallopamil available under the tradename of Procorum®. Therapeutic dose range in cardiology: 3 X 25 mgs to 4 X 50 mgs/day orally.

Vasoconstrictor and vasodilator substances, their effect on arterial preparations

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Verapamil

2,5*10-5

Fig. 1

mol/I

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Concentration-response curves for verapamil action on carotid artery of rat after serotonin activation.

account of the significantly greater effect of D 600-HCL in equimolar dosage we decided to continue the experiments using this substance solely and the concentration used was 4.8 X 10~4 mol/1. The following problems were investigated: 1. Is a vasodilator effect observable in intracranial vessels? 2. Can an additional vasodilator effect, exceeding 100%, be observed with the method employed? A significant vasodilator action was found for the basilar artery. In addition higher values than the previously recorded were noted for vasodilation and the effect of serotonin was not only completely antagonised but the perfusion pressure could be lowered by about 149% (fig. 3).

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M. Henn D 600-HQ

Fig. 2

Concentration-response curves for D 600-HCL action on carotid artery of rat after serotonin activation.

Discussion We assume that serotonin has a definite influence on the early phase of developing angiospasm. Its vasoconstrictor effect, can be antagonized by Ca 2 + antagonists verapamil and D 600-HCL as could be shown in vitro. Whether the expected side effects on the heart muscle, when using high doses, will prohibit the application cannot be forcasted by these experiments and can be answered by clinical studies only. We believe that the methods developed and reported at this meeting will allow studies of intra-cranial vasculatur in vitro. In particular the application of a constant

Vasoconstrictor and vasodilator substances, their effect on arterial preparations

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A. basilaris Kaninchen

Sero

Imbarl

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tonin

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Constant flow preparation of the basilar artery of rabbit. Note decrease of perfusion pressure by D 6 0 0 - H C L after previous activation with serotonin.

flow preparation should produce better results for allowing cautious conclusions for in vivo situations than the examination of vascular strips under isometric conditions [1, 3, 10]. In view of the small sizes of the vessels a considerable micro-surgical skill has to be used to gain successful preparations. However once these technical difficulties have been overcome, we believe that future experiments using constant flow preparations can yield promising results.

Summary The common carotid and internal carotid arteries of rat and the basilar artery of rabbit were examined using stripes of these vessels as a constant flow preparation and under isometric conditions. We concentrated on the effects of calcium antagonists. The findings under isometric conditions are as follows: Without an initial vasoconstrictor stimulus Ca 2 + antagonists excercise no effect. Verapamil antago-

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nizes at the highest dose, the vasoconstrictor effect caused by serotonin at a value of 6 2 % . D 6 0 0 - H C L antagonizes vasoconstriction at the highest dose completely (100%). Under conditions of a constant flow preparation, the following findings could be made: In this type of preparation the basilar artery exhibits the expected vasodilation. In contrast to isometric measurements the starting values did not come up to expected values and the perfusion pressure decreased about a 1 4 9 % .

References [1] Allen, G. S. and L. M . Henderson: Cerebral arterial spasm: Part 1. In vitro contractile activity of vasoactive agents on canine basilar and middle cerebral arteries. J . Neurosurg., 4 0 , 433—441 (1974). [2] Chapleau, C. E. and R. P. White: Effects of prostacyclin synthetase inhibitors (PSI) on contractions induced by arachidonate, prostaglandin F 2-alpha and serotonin in basilar arteries. Fed. Proc. 38, 3 5 9 (1979). [3] Edvinsson, L. and J . E. Hardebo: Pharmacological analysis of 5-hydroxytryptamine receptors in isolated intracranial and extracranial vessels of cat and man. Circ. Res., 4 2 , 143—151 (1977). [4] Edvinsson, L. and Ch. Owman: Cerebrovascular nerves and vasomotor receptors. In: R. H. Wilkins, Cerebral Arterial Spasm, pp. 30—36. William Sc Wilkins, Baltimore-London 1 9 8 0 . [5] Forster, Ch. and J . Mohan: Interaction of fibrin degradation products and 5-hydroxytryptamine on various vascular smooth muscle preparations. In: R. H. Wilkins, Cerebral Arterial Spasm, pp. 1 8 6 - 1 8 9 . William &c Wilkins, Baltimore-London 1980. [6] Miiller-Schweinitzer, E.: Effects of calcium antagonists PN 2 0 0 - 1 1 0 , nifedipine, and nimodipine on human and canine cerebral arteries. J . Cereb. Blood Flow Metabol., 3, 354—362 (1983). [7] Scremin, O. U. and R. R. Sonnenschein: Cerebrovascular anatomy and blood flow measurement in the rabbit. J . Cereb. Blood Flow Metabol., 2, 5 5 - 6 6 (1982). [8] Simeone, F. A. and Ph. E. Vinall: Evaluation of animal models of cerebral vasospasm. In: R. H. Wilkins, Cerebral Arterial Spasm, 2 8 4 - 2 8 6 . William & Wilkins, Baltimore-London 1980. [9] Uchida, E. and D. F. Bohr: A method for studying isolated resistance vessels from rabbit mesentery and brain and their responses to drugs. Circ. Res., 21, 525—536 (1967). [10] Wahl, M . and A. R. Young: Effects of kinase II inhibitors on vasomotor response to bradykinin of feline intracranial and extracranial arteries in vitro and in situ. J . Cereb. Blood Flow Metabol., 3, 3 3 9 - 3 4 6 (1983). [11] Wilkins, R. H.: Attempted prevention or treatment of intracranial arterial spasm: A survey. In: R. H. Wilkins, Cerebral Arterial Spasm, pp. 5 4 2 - 5 5 5 . William &C Wilkins, Baltimore-London 1980.

The influence of peripheral and central monoamine systems on the development of experimental cerebral vasospasm in rats N. A. Svendgaard, J. Brismar, T. Delgado, N. Diemer

Introduction It has been suggested by a number of authors that monoamines are involved in the development of cerebral vasospasm after a subarachnoid haemorrhage (SAH) [1, 3 , 6, 7, 12 and 13]. Our earlier studies of experimental SAH in rabbits have shown a reduction in the number and the fluorescence intensity of the visible perivascular adrenergic nerves of the major cerebral arteries following a cisternal blood injection. In addition the neuronal uptake of noradrenaline (NA) is reduced [10]. These changes run parallel to the development of angiographically visible vasoconstriction. Furthermore, in in vitro studies there is an increased sensitivity of the basilar artery to N A and 5-hydroxytryptamine (5-HT) following the experimental SAH [11]. Our aim has been to examine more closely the possible role of both peripheral and central monoamines for the development of cerebral vasospasm.

Material and methods The experiments were performed on male Sprague-Dawley rats (SPF strain M0llegaards Avlslaboratorium, Kjage, Denmark) weighing between 2 8 0 and 4 0 0 grams.

Experimental SAH model Homologous blood ( 0 . 0 7 - 0 . 1 ml) was injected intracisternally via a previously implanted catheter connected to the cisterna magna. The effect of the cisternal blood injection was evaluated with vertebro-basilar angiography and double autoradiographic determination of local cerebral blood flow (CBF) and glucose metabolism (CMRgl). The animals were intubated and artificially ventilated with a nitrous-oxide and oxygen mixture. During the surgical procedures, halothane ( 0 . 7 5 % ) was added to the gas mixture.

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Angiography Vertebro-basilar angiography was performed via bilateral axillary catheters. Metrizamide (Amipaque®, Nygaard and Co., Oslo, Norway) was used as the contrast medium. Measurements of the vertebral and basilar diametres were made according to the method described by Gabrielsen and Greitz. The values of four preselected points within the vertebro-basilar system were averaged and then expressed as a percentage of control values (see fig. 1). The animals were examined pre-SAH and at the following time points post-SAH: 5 , 1 0 , 1 5 , 30, 60, 90 minutes and 1, 2 , 3 , 5, and 7 days. There was a biphasic patterns of vasospasm. The acute spasm was maximal after ten minutes and the late maximal spasm two days post SAH (see fig. 2). CBF and CMRgl Simultaneous determinations of CBF [8, 5] and CMRgl [9] were made using 1 4 Ciodoantipyrine and 3 H-deoxyglucose, respectively, according to the double autoradiographic method of Diemer and Rosenorn [2]. The examinations were performed in animals artificially ventilated with a nitrous-oxide and oxygen mixture two days post SAH. The animals were injected intravenously with 750 piCi 3 H-deoxyglucose. During a circulation time of 45 minutes, blood samples were taken for the determination of the deoxyglucose-plasma integral. After the last deoxyglucose sample, the arterial catheter was connected to a constant velocity withdrawal pump. Simultaneously 60 (iCi of 14 C-iodoantipyrine was injected as an intravenous bolus. After 20 seconds, the animal was decapitated and the brain frozen. The integral for arterial 14 C-iodoantipyrine was determined for the 20 seconds period. The double autoradiograms were made from two adjacent sections after extracting the 14 C-iodoantipyrine with 2.2 dimethoxypropane.

Lesions of the peripheral monoamine systems Barbiturate anaesthesia (Brietal®, Lilly 40 mg/kg i.p.) was used for the lesioning procedures. Adrenal demedullation Bilateral adrenal demedullation was carried out by removal of the adrenal glands. Cranial sympathectomy This was performed by bilateral removal of the superior cervical ganglia. Chemical sympathectomy In adult rats, 6-hydroxydopamine (6-OHDA 100 mg/kg) was given intravenously. This compound is taken up into the sympathetic nerve fibres causing a selective and

Fig. 1

Bilateral vertebral angiography of a rat showing the sites (small arrows) at which vertebral and basilar artery diametres were measured: 0.5 cm proximal to the vertebro-basilar junction on the vertebral arteries; on the basilar artery 0.5 cm above the junction of the vertebral arteries and 0.5 cm below the origin of the posterior cerebral arteries. An index was calculated as the mean values of the measured diametres. Axillary catheters are indicated by a big arrow. Axial view, magnification 2.88.

N. A. Svendgaard, J. Brismar, T. Delgado and N. Diemer

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acute adrenergic denervation. The adrenal medullary cells are not affected by the 6-OHDA and the compound does not penetrate the blood brain barrier. In newborn animals, 6-OHDA (100 mg/kg at day zero, one and two after birth) was given subcutaneously. At that time, the blood-brain-barrier had not yet developed.

Stereotactic lesions of the central monoamine systems Barbiturate anaesthesia was again used. Lesion of the 5-hydroxytryptamine systems The lesion was produced by a single injection of 150 [xg 5.7 dihydroxytryptamine creatinine sulfate (Rigis Chemical and Co., USA) into one lateral ventricle. Bilateral lesions of the nigrostriatal dopamine (DA) pathways The lesions were made rostromedially to the substantia nigra where the nigrostriatal, mesolimbic and mesocortical DA pathways assemble. The lesions were produced by injection of 6-OHDA (8 ^g in 4 of saline) at the following coordinates: 4.5 mm behind the bregma, 1.1 mm lateral to the midline and 8 mm below the dura. The toothbar was kept 3 mm below the interaural line.

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Bilateral lesions of the ascending catecholamine (CA) pathways in the mesencephalon The ascending catecholamine fibres from the medulla oblongata and pons were lesioned at the level of the caudal mesencephalon rostral to the subcoeruleus area (see fig. 3, lesion 1). The lesions were produced with a bilateral injection of 6-OHDA (8 |ig in 4 jxl of saline). With the toothbar at zero, the following coordinates were used: 0.5 mm rostral to the interaural line. 1.1 mm lateral to the midline and 6. mm down from the dura. Bilateral lesion of the locus coeruleus (LC) in the pons The CA containing neurons in the LC were destroyed electrothermically using a radiofrequency lesion generator (RFG4A, Radionics, Burlington, Mass., USA). The following coordinates were used: toothbar at zero, 0.7 mm caudal to the interaural line, 1.1 mm lateral to the midline and 6.4 mm below the dura (see fig. 3, lesion 2).

Bilateral lesions of the ascending CA fibres from Ai and A2 in the medulla oblongata The lesions were produced by injection of 6-OHDA (6 |ig in 3 [0.1 of saline at 7.2 and 8 mm below the dura, respectively). The toothbar was kept at zero and the other coordinates were: 2.3 mm caudal to the interaural line and 1.1 mm lateral to the midline (see fig. 3, lesion 3).

Sham lesions Sham lesions were made for all the experimental groups.

Control of lesions In the demedullated animals the adrenal glands were examined with fluorescence microscopy and in the animals subjected to surgical or chemical sympathectomy, the irides were examined likewise. The lesion of the dopaminergic system was checked by analysis of the DA content of the caudate-putamen. The lesion of the CA pathways in the mesencephalon was controlled by analysis of the NA content in the frontal cortex and with fluorescence histochemistry of the hypothalamus.

132

Fig. 3

N . A. Svendgaard, J. Brismar, T . Delgado and N. Diemer

Schematic illustration of the dopaminergic and noradrenergic pathways in the rat brain showing also the different lesion sites.

The LC lesion was controlled with fluorescence microscopical examination of the lesion site. The lesion of the ascending fibres from Ai and A2 was checked with determination of the NA content of the frontal cortex and the diencephalon. In three animals, the injection site was examined fluorescence microscopically, and it was noted that the LC was intact.

Experimental design All lesions were made at least two weeks before the experimental SAH in all the groups with the exception of the neonatally treated animals that were evaluated 2—4 months after the injection of 6-OHDA. Angiography was carried out after ten minutes and two days post SAH in six animals in each group. (In the LC group there were only three animals.) CBF and CMRgl studies were performed two days post SAH in normal animals and in animals with lesions of the ascending CA pathways in the mesencephalon.

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Results The physiological parameters measured were temperature, mean arterial blood pressure (MABP), pulse rate, p H , PaC>2 and PaCC>2. T h e temperature was kept close to 3 7 ° by using a heating blanket. Generally in all the experimental groups there was a minor decrease in M A B P and pulse rate after ten minutes and two days post SAH. These changes were not significant. T h e p H values were close to 7 . 4 . T h e P a C O i values were about 1 5 0 mm H g and the PaCCh values were around 3 7 m m Hg. The animals with late spasm were noticeably drowsy and passive, but no paralysis was noted. T h e sham lesioned animals showed the same degree of spasm post SAH as normal animals allowing the values from the sham lesioned animals to be pooled. Cisternal blood injection in the animals with adrenal lesions produced a reduced spasm after both ten minutes and two days as compared to sham lesioned animals. However, the change appears not to be significant (see fig. 4). Mean vessel diametre % of control

10 minutes after SAH THE V A L U E S Fig. 4

2 days after SAH

one animal had a complete bilateral adrenalectomy

ARE MEANS i S.E.M.

Angiographical changes in vertebro-basilar diameter post SAH after lesions of the peripheral monoamine systems. The values are mean ± S E M in per cent of control. * p < 0 . 0 5 , * * p < 0 . 0 1 , ***p-). a) Right carotid angiogram, oblique projection, b) left carotid angiogram, oblique projection: spasm of right anterior cerebral artery (—»); the aneurysm is only visible in the left carotid angiogram.

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E. Schindler

wall. Narrowing of basal brain arteries can be seen in cases of tuberculous meningitis [3]. It is not possible to discriminate angiographically between spasm and vascular hypoplasia. Spasm can exhibit occasionally a "beaded" vascular pattern [1] causing great difficulty in deciding whether this pattern is due to an atheromatosis or due to spasm. Fibro-muscular dysplasia of intracranial vessels [5] — although very seldom — can produce also "beaded" arteries. Spasm of cerebral vessels occurs most often after subarachnoidal haemorrhage following rupture of an aneurysm. Wilkins and co-workers [10] demonstrated vasospasm in 47% of patients after bleeding from aneurysm, but in only 6.4% of those patients suffering from subarachnoidal haemorrhage caused by head injury. Sometimes intracranial angiospasm is triggered by head trauma [4]. Angiography is known causing cerebral vascular spasm, e.g. by puncturing the carotid artery and sub-intimal injection of contrast medium or after catheter angiography (fig. 4). It is likely that the spasm is triggered by pushing too much forward the catheter or the leading wire, it may also be caused by a too hard or too thick catheter. Subarachnoidal haemorrhage and angiospasm are interrelated in time and cause, but it is still unclear what finally causes the spasm. The vasospasm usually appears three or four days after the rupture of the aneurysm and can last for weeks. Occasionally, however, spastic arteries appear immediately after the bleeding [8]. The findings of an angiospasm in an angiogram made several weeks later may be due to a second bleeding [1] or due to changes of the vessel wall — Mizukami and co-workers [8] demonstrated histologically in cases of "chronic spasm" that the narrowing of the lumen was caused by a fibrosis of the intima.

Fig. 2

Aneurysm of right middle cerebral artery (-*•); subarachnoidal haemorrhage and haematoma in the right temporal lobe (proven by CT), causing shifting of vessels. Diffuse spasm of frontoparietal branches of the middle cerebral artery (—>); the anterior cerebral artery is not visualized; due to the space occupying haematoma the posterior communicating artery is pushed against the dorsum sellae and narrowed (—>).

Neuroradiological aspects of cerebral angiospasm

275

Localization and degree of angiospasm after subarachnoidal haemorrhage are very different. In some cases only one vessel segment is narrowed, in others a diffuse vasospasm is present and a number of cerebral arteries is involved. A constant relationship between the extent of subarachnoidal haemorrhage and the degree of spasm seems not to exist. The angiogram can show a minimal, local spasm or even a normal vascular pattern, whereas CT yields extensive bleeding into the CSF spaces. On the other hand a diffuse spasm may be seen angiographically but the bleeding is hardly verifiable in CT. Supra-tentorial aneurysms produce spasm more frequently than aneurysms of the vertebro-basilar system [4], but there is no constant localizing connexion between the ruptured aneurysm and the spastic vessel. The spasm can be located distally or proximally from the aneurysm. Often a neighbouring artery is spastic, but a distant single vessel segment may also be found spastic. Sometimes a spasm is found in the contralateral arteries — therefore, in many cases an aneurysm of the anterior communicating artery is visualized only if the angiography is made on that side, where the vessels are not narrowed (fig. 1). When the source of a subarachnoidal haemorrhage is searched and several aneurysms have been found, the site of the spasm does not allow to conclude which aneurysm has bled. The question whether the spasm of a certain brain artery causes corresponding neurological focal signs, cannot be unequivocally answered. The neurological status may be normal, even though the angiogram shows distinct spasms, whereas severe neurological deficits may exist though the vessels appear normal. Hence it is not possible to draw any firm conclusion from neurological signs, which vessel has become spastic. Nor it is possible in each case to correlate the results of cerebral blood flow measurements with the neuroradiological findings. Severe and long lasting spasms, however, can cause infarcts [4] and lead to manifest corresponding signs — in such cases CT follow-up studies are indicated. But based on a study of hundred patients with angiographically proven angiospasm Millikan [7] states, that no significant relation between vasospasm and clinical signs can be established. The objection has to be raised, that angiographically demonstrated spasms are more frequent in those patients who exhibit neurological signs or disturbance of consciousness, than in patients with normal neurological state and no impairment of consciousness. However, since many cases occur where the clinical findings do not agree with the neuroradiological ones, one should use the term "spasm" only if it is proved angiographically — "cerebral angiospasm" should be a neuroradiological diagnosis. Although the cerebral angiospasm can be ascertained or excluded by angiography, it is questionable whether or not this examination is indicated to confirm the clinical suspicion of spasm. This is because of the fact that angiography can cause more often — and sometimes more serious — complications in patients with spastic cerebral arteries than in patients with normal vessels. The exact percentage of such compli-

276

E. Schindler

cations cannot be given — a statistical assertion could only be valuable, if there would be evidence in each case that the incidence was caused by the angiography, this causal connexion is impossible to prove in the single case. If one, however, surveys those patients with subarachnoidal haemorrhage, who deteriorated after angiography, and evaluates their angiograms, one finds spastic cerebral vessels in the majority of cases. Only in few of these cases the worsening of the clinical condition can directly be related to the angiographical technique (fig. 4). In other cases, it seems reasonable to assume that cerebral regions with already decreased blood supply because of spasm have been additionally injured by angiography, and therefore their function cannot be maintained. This additional injury could be due to a temporary regional hypoxia during the contrast medium perfusion — all the more so, as the circulation time is increased in cases of vascular spasm after rupture of an aneurysm [9]. From this it can be concluded, that the risk of a complication is greater the more contrast medium is administered. Consequently, Allcock [1] emphasizes that "if spasm is severe, the quantity of contrast medium injected should be as small as possible and additional views should not be obtained unless they are absolutely necessary".

Fig. 4

Cerebral angiospasm (—») seen in catheter angiography. Kinking of internal carotid artery at the level of the second cervical vertebra. The spasm could be produced by the tip of the catheter (»•) pushed forward into the kinking.

Neuroradiological aspects of cerebral angiospasm

277

The angiography in a patient with subarachnoidal haemorrhage is not indicated to prove the angiospasm but to find the source of bleeding. In each case the patient's condition has to be considered, as well as the therapeutic consequence — if the patient's condition does not allow a neurosurgical intervention, angiography should not be performed. The regional cerebral blood flow measurement can help in deciding whether angiography is indicated - as long as there is an obviously reduced blood flow, angiography should be postponed. Ultrasonic examinations also may supply informations concerning caliber and blood flow of cerebral arteries, these informations may influence the indication for angiography as well. CT is absolutely indicated for proving subarachnoidal haemorrhage, but it is incapable in showing angiospasm. CT may show a hypodense area indicating a hypoxic oedema, but without further controls no decision can be reached whether this is due to vasospasm or to a developing infarct. It is possible that an aneurysm is better visible if neighbouring vessels are spastic [4], but it is also possible that the aneurysm does not fill with contrast medium because the feeding vessel is spastic [1]. It must be emphasized that angiography carries greater risk, if spasm does exist. For this reason one has to ask whether the patient would be better off, if the angiography would be called off - in particular if the first angiographic series show severe spasm, it would be better to defer further series. In any case the repeated injection of contrast medium into a spastic vascular region should be omitted. If the suspicion of an aneurysm has to be verified, visualization of all cerebral arteries is necessary, sometimes even in different projections - by doing so, a large amount of contrast medium may be necessary. In cases of severe spasm of a certain vascular region, the neuroradiologist should refrain from angiography of the other vessels, in particular if the neurosurgeon does not intent operating due to the vasospasm. It is not uncommon that the control angiography after operation of the aneurysm reveals an angiospasm. This can be caused by renewed bleeding or by the irritation of the vessel due to the preparation of the aneurysm for clipping. But angiospasm can also occur after an uncomplicated operation (fig. 3). Since the post-operative spasm may last for a considerable time, a control angiography — if deemed necessary to check the position of the clip around the neck of the aneurysm — should be postponed for several weeks. The problem whether a spasm is still present can be solved also by intravenous digital substraction angiography [2]. To evaluate a particular method of investigation it is not sufficient to balance its diagnostic reliability against the rate of its possible complications. A more important criterion is the question, whether this diagnostic method supplies informations that are decisive for the planning of therapy or not. Considering the neuroradiological aspects of cerebral angiospasm, the challenge is posed, what is the significance of the angiographic diagnosis of spasm. On the one hand angiography is essential for verifying cerebral angiospasm, but on the other hand angiography can cause com-

278

Fig. 3

E. Schindler

Aneurysm of left middle cerebral artery (">•). a) Preoperative left carotid angiogram: slightly diminished caliber of the internal carotid artery (supraclinoid portion), b) Left carotid angiogram, two weeks after operation: severe spasm of internal carotid artery (—») (no clinical signs of recurrent haemorrhage).

plications all the more if spasm does exist. The clinician, however, will carry out the same treatment in patients whose disease, clinical condition and neurological findings will raise the suspicion of cerebral angiospasm, as he will do so in patients with angiographically proven spasm.

Summary Angiography is the best method for proving cerebral angiospasm, although other vascular changes are to be considered when narrowed arteries are found. Angiospasm is usually the sequel of subarachnoidal haemorrhage after rupture of an aneurysm. A constant relationship cannot be established between the site of the

Neuroradiological aspects of cerebral angiospasm

279

aneurysm and the extent of the haemorrhage on the one hand, and the localization and degree of the angiospasm on the other. The patient's clinical condition does not necessarily correspond with the neuroradiological findings. In cases of subarachnoidal haemorrhage angiography is not indicated to determine an angiospasm, but to ascertain the source of bleeding. It is to be considered that angiography can cause complications particularly in patients with spastic cerebral arteries. The decision for angiography must be subject to the patient's clinical condition in each case, furthermore the results of other examinations are to be taken into account. If the clinical condition or the results of cerebral blood flow measurement indicate a severe spasm, no angiography should be carried out, since the treatment would be the same whether angiospasm is angiographically confirmed or not.

References [1] Allcock, J. M.: Aneurysms. In: T. H. Newton, D. G. Potts (eds.), Radiology of the Skull and Brain. Vol. 2, Book 4. C. V. Mosby, St. Louis 1974. [2] DeFilipp, G. J., R. S. Pinto, J. P. Lin and 1.1. Kricheff: Intravenous digital subtraction angiography in the investigation of intracranial disease. Radiology 148, 129—136 (1983). [3] Greitz, T.: Angiography in tuberculous meningitis. Acta radiol. (Diagn.) 2, 369-378 (1964). [4] Huber, P.: Zerebrale Angiographic fur Klinik und Praxis. Thieme, Stuttgart 1979. [5] Iosue, A., E. L. Kier and D. Ostrow: Fibromuscular dysplasia involving the intracranial vessels. Case report. J. Neurosurg. 37, 7 4 9 - 7 5 2 (1972). [6] Launay, M., D. Fredy, J. J. Merland and J. Bories: Narrowing and occlusion of arteries by intracranial tumors. Neuroradiology 14, 117-126 (1977). [7] Millikan, C. H.: Clinical state of patients with cerebral vasospasm. In: J. P. Whisnant, B. A. Sandok (eds.), Cerebral Vascular Diseases. Grune &C Stratton, New York 1975. [8] Mizukami, M., H. Kin, G. Araki, H. Mihara and Y. Yoshida: Is angiographic spasm real spasm? Acta neurochir. 34, 2 4 7 - 2 5 9 (1976). [9] Okawara, S., J. Hahn and J. Kimura: Cerebral circulation time and ruptured intracranial aneurysm. In: K. Kitamura, T. H. Newton (eds.), Recent Advances in Diagnostic Neuroradiology. Igaku Shoin, Tokio 1975. [10] Wilkins, R. H. and J. A. Alexander: Intracranial arterial spasm: a clinical analysis. J. Neurosurg. 29, 121-134 (1968).

Cerebral angiospasm: differential diagnostic considerations A. Ahyai, K. Rittmeyer, O. Spoerri

Introduction It is still a matter of controversy when in patients with subarachnoidal or intracerebral haemorrhages, angiography, still indispensable in a neurosurgery procedure, should be performed. The angiospasm, which can either be induced by subarachnoidal haemorrhage, or even provoked by angiography, is often accused of being the cause of considerable worsening in the patient's general condition after angiographic examination. Furthermore, if radiologically evident, the presence of angiospasm is awarded a prognostic importance. The discussion, whether the patients should be angiographed shortly after haemorrhage, or later on during the symptom free period, is guided, either by considering different techniques for demonstrating vascular lesions (aneurysms), or by the risk the angiographic examination presents in choosing the right time following the haemorrhage [1, 2, 3]. The fear that the patient's condition following angiography might severely deteriorate, or even die, confronts the clinician with an alternative of waiting, or risking a further haemorrhage.

Methods It was for these reasons, that the neurological and neurosurgical histories of patients with either subarachnoidal, or intra-cerebral haemorrhages, were investigated. These investigations carried out with the view wether the angiospasm can be related to clinical parameters, e.g. the state of consciousness at the time of angiography. The appearance of an angiospasm in the angiogram of some parts of extracranial vessels should not cause problems, for this is due largely to temporary mechanical irritation. There should be no difficulties in the differential diagnosis whether the picture is that of reactive/degenerative vascular wall diseases, feigning angiospasm. In circumscribed or more extended changes in the calibre of intracranial vascular portions, however, the differential diagnostic distinction has to be made between

282

A. Ahyai, K . Rittmeyer a n d O . Spoerri

angiospasms, vascular compression (due to increased intracranial pressure) and degenerative vascular wall diseases. In order not to endanger the patient with further angiography, a vascular change should be clearly identified, particularly if a bilateral angiography is required, which is frequently necessary to prove the existence of an intracranial aneurysm (in one or two sessions). Bearing this in mind, we first reviewed 57 patients with subarachnoidal haemorrhages (46 verified aneurysms) and 18 patients with intracranial haemorrhages, regarding the frequency of angiospasms.

Results A varying distribution of spastically altered vascular portions is obviously dependent upon the localization of the aneurysm. Altogether, we observed an average of 54% of angiospasm in ruptured aneurysms during the 1st three weeks. This is in agreement with the observations of Maspes and Marini [4], who found a frequency of spasms of 51% within the 1st month. The frequency of distribution of angiospasms following aneurysms affecting the anterior and posterior communicating arteries and of the middle cerebral artery

Table 1

T h e distribution of v a s o s p a s m s dependent on the localisation of the a n e u r y s m during the first a n d s e c o n d week after S A H

Subarachnoid hamorrhage ant. comm. a. aneurysm

Angiography day 1—7 Spasm no Spasm

n 7

(n = 13) Middle cerebral a. 11 aneurysm (n = 13) post. comm. a. 9 aneurysm (n = 12) int. carotid a. 5 aneurysm (n = 5) ant. cerebral a. 2 aneurysm (n = 3) no aneurysm 8 (n = 11) n = 57

n = 42

Angiography day 8-14 Spasm no Spasm

n

n

Angiography day 15-21 Spasm no Spasm

4

3

4

4

2

2

9

2

2

0

4

5

1

1

2

3

2

0

1

1

1

1

6

2

2

1

1

1

n = 9

n = 1

n -5n = 4

n = 20

n = 22

n = 10

1

1

2

0

0

1

n = 1

Cerebral angiospasm: differential diagnostic considerations

283

during the 1st three weeks after subarachnoidal bleeding, is shown in the table 1. On the whole, spasms were most frequently seen during the first three weeks following aneurysms of the anterior and posterior arteries and of the carotid siphon; whereas the number of spasms following aneurysms of the middle cerebral artery was distinctly reduced during this period. Huber et al. [1] conclude that spasms occur most frequently in aneurysms of the anterior communicating artery, the middle cerebral artery and the carotid bifurcation, whilst they were less frequently found in aneurysms of the posterior communicating artery. A certain trend in the varying localisations of aneurysms can be recognized: Both in the aneurysms of the anterior communicating artery and in those located in the region of the middle cerebral artery, there appears to be a particular risk of angiospasm in the second week. In contrast, however, differences appear in the first week following subarachnoidal haemorrhage. It can be found than that the expectance of an angiospasm following aneurysms of the middle cerebral artery is less than for the anterior communicating artery. This trend found in our cases contradicts claims made in the literature [1]. Interestingly enough, some of the patients with identified subarachnoidal haemorrhage, but with no demonstrable source of bleeding, showed an increased tendency towards spasm in the first week but we cannot offer an explanation. The wide-spread opinion that angiography becomes less of a risk to patients, the longer the interval between investigation and occurrence of the haemorrhage, has to be viewed with caution, for there is a diminished tendency towards angiospasms in patients, where the aneurysm is localized in the middle cerebral artery.

Discussion It is now possible to locate the source of bleeding by using routine computerised tomography in most patients with an intra-cranial haemorrhage and the source of bleeding can be localized in a definite vascular area after the application of contrast medium in the CT. Another debatable point is the observation that the patient's state of consciousness appears to have no definite influence on the tendency towards spasms. In a total of 18 intracerebral haematomas, there was merely one single case that had a highgraded spasm of the Al portion. In 9 patients, a reduction of the arterial calibre as a consequence of intracranial pressure could be ascertained, which could feign the picture of an angiospasm. The time of angiography, state of consciousness and hypertonia, showed no direct connection with the angiospasm. The following illustrations, figures 1 and 2, serve as explanations.

284

A. Ahyai, K. Rittmeyer and O. Spoerri

Fig. 1

Segmental angiospasm in the immediate proximity of the middle cerebral aneurysm, caused by subarachnoidal haemorrhage.

Fig. 2

In contrast with the segmented angiospasm, there is the annular constriction of the carotid siphon. The anterior clinoidal process evidently causes a mechanical obstruction in a left temporal mass haemorrhage with consecutive displacement of the middle cerebral artery and ventral displacement of the carotid siphon.

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285

Summary Angiospasms, caused by subarachnoidal haemorrhage or by angiographic verification of the source of bleeding, can endanger the patient greatly for this reason, the time chosen for vascular examination is of great significance. 57 patients with subarachnoidal haemorrhage (46 verified aneurysms) and 18 patients with intra-cranial haemorrhage were investigated for angiospasm. Altogether, approximately 54% of the spasms were found in vessels with ruptured aneurysms during the first three weeks. A varying distribution of spastically altered vessels is evidently dependent upon the localization of the aneurysm. Spasms were most frequently found in the course of the first three weeks in aneurysms of the anterior and posterior communicating arteries, as well as in those of the carotid siphon. On the contrary, the number of spasms in aneurysms of the middle cerebral artery proved to be significantly less during this period. An increased tendency towards angiospasm, particularly in the 1st week, could be seen in patients with a definite subarachnoidal haemorrhage, whose angiogram, however, failed to demonstrate the source of bleeding. In view of the importance of a reliable identification of an angiospasm, particularly when a decision has to be made for bilateral angiography, differential diagnostic considerations are essential. A connection between the patient's state of consciousness at the time of angiography and the tendency towards angiospasm could not be ascertained.

References [1] Huber, P., H. Krayenbühl und M. G. Yasargil: Zerebrale Angiographie für Klinik und Praxis. Georg Thieme-Verlag, Stuttgart 1979. [2] Krayenbühl, H. und M . G. Yasargil: Zerebrale Angiographie. Georg Thieme-Verlag, Stuttgart 1965. [3] Krayenbühl, H. und M . G. Yasargil: Klinik der Gefäßmißbildungen und Gefäßfisteln. Der Hirnkreislauf: Physiologie, Pathologie, Klinik. 4 6 5 - 5 1 1 . Georg Thieme-Verlag, Stuttgart 1972. [4] Maspes, P. E. and G. Marini: Intracranial arterial spasm related to supraclinoid ruptured aneurysms. Acta Neurochir. (Wien). 10, 6 3 0 - 6 3 8 (1962).

Noninvasive transcranial Doppler ultrasound recording in basal cerebral arteries — a new approach to the evaluation of cerebrovascular spasm R. Aaslid, P. Huber, H. Nornes

Introduction Cerebral vasospasm causes an increase of the flow energy losses in the arteries supplying the brain. Normally, the cerebral circulation is auto-regulated, and a moderate increase in the flow resistance of a spastic segment is compensated for by dilatation of the intra-parenchymatous contractile vessels. Thus cerebral blood flow (CBF) is maintained at practically constant levels, and measurements of CBF are likely to reveal the effect of spasm only in a critical stage when the compensatory capacity of the vaso-regulatory mechanism has been exhausted. Most patients with subarachnoid haemorrhage (SAH) probably never enter this stage, although their cerebral arteries may exhibit some degree of spasm in angiography. There is a need for a method that can be used to evaluate cerebral vasospasm in all stages and to monitor its onset and resolution in the individual patient; unfortunately, angiography is an invasive procedure which is unsuitable for repetition with frequent intervals. Narrowing of the arterial flow lumen is followed by an increase in flow velocity [4, 6]. This principle is routinely used for noninvasive diagnosis of stenosis of the extracranial carotid artery, and it is sensitive to arterial narrowing long before volume flow is significantly affected [8]. Recent developments in Doppler ultrasound techniques permit the recording of flow velocity in the intracranial basal cerebral arteries [2], The method has been applied to patients with SAH to evaluate vasospasm [1]. This report presents the methodological basis of the approach with examples from a series of 40 patients with spontaneous SAH recorded at the Clinic of Neurosurgery in Berne.

288

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Methods The Doppler instrument has an ultrasonic frequency of 2 MHz and operates in pulsed range-gated mode. The distance or depth from the transducer to the sampling-volume can be selected by the operator in stepts of 5 mm over a range from 25 to 100 mm. The diameter of the transducer is 16 mm and the acoustic output power is 100 mW/cm 2 . A polystyrene lens which is glued on to the transducer, focuses the ultrasonic beam at depths of about 50 mm. Therefore, the instrument is sensitive only to velocities within the relatively small sampling volume, approximately 10 mm in length (depth) and 4 mm in diameter. The Doppler shifted signals are displayed on a real-time spectrum analyzer with direction discrimination. The velocity readings are taken with a cursor from the frozen spectral display; we have chosen the timemean of the spectral outline (maximal instantaneous Doppler shift) to quantify flow velocity [2]. The first step in the Doppler examination is to locate the most suitable area of the cranium for penetration of ultrasound. It is usually found in the temporal region just above the zygomatic arc; this region is searched for Doppler signals with a depth setting of 50 or 55 mm. The position giving the strongest signals is selected for further recordings. In about 5 % of the cases we have not been able to achieve a sufficient signal to noise ratio of the Doppler signals, all these cases were elderly women. At depths between 55 and 65 mm the siphon of the internal carotid artery (ICA), the middle (MCA), anterior (ACA) and the posterior (PCA) cerebral arteries produce a variety of Doppler signals depending on the aiming of the ultrasonic probe. The most difficult part of the trans-cranial Doppler investigation is the identification of the artery producing the Doppler signals. To achieve this, a depth scanning technique is used. Anatomically, the MCA is nearly always the only main artery that runs laterally outwards from the carotid siphon. Therefore, it is the most easy to identify using the depth control to scan outwards as well as inwards between 30 and 55 mm, tracking the course of the artery by small angle movements of the ultrasonic probe. The signals from the carotid siphon, the PCA and the ACA, in contrast, are lost when scanning outwards beyond approximately 55 mm. The ACA is identified by scanning the MCA progressively deeper until, at depths of about 60 mm, the signal grows weaker and a Doppler shift in the opposite direction is found. We have not yet obtained good signals from the pericallosal arteries, these have an unfavourable course for Doppler recording from the temporal region. The PCA is found by searching the region posteriorly to the MCA and ACA at depths between 75 and 60 mm. The carotid siphon is identified by first directing the sampling volume to the region where both the MCA and the ACA signals are found, and then aiming the probe slightly caudally and anteriorly. The signal from this region usually has a lower Doppler shift and a "gruffy" audible quality. The blunt angles of insonation give rise

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289

to Doppler shifts that may be considerably lower than the real velocity in the siphon. In contrast, the MCA — and most often also the ACA — are very favourably situated for Doppler recording, coming practically either directly towards or away from the transducer placed in the temporal region. A rough estimate of the insonation angle can be onbtained by noting the amount of angle movement necessary to track the MCA outwards from 55 to 35 mm. In our experience, the area just behind the frontal process of the zygomatic bone is the most favourable location for recording in the proximal part of the MCA (if penetration of ultrasound is possible there). We also record the flow velocity in the extracranial ICA. In order to minimize the errors due to the angle of insonation, an attempt is made to aim at the artery at sharp angles (when the angle is below 30 degrees, the error is less than 15%). The probe is held below the mandible and the depth is set to about 40 mm.

Results In a group of 50 subjects without any evidence of cerebro-vascular disease we found flow velocities in the MCA's ranging between 35 and 85 cm/sec [2]; the mean in this series was 62 cm/sec and the standard deviation was 12 cm/sec. The flow velocities in MCA's of patients with SAH nearly always reached levels of 100 cm/sec or more during the first two weeks after the bleeding. Five patients had arterial narrowing which was diagnosed as spasms at the time of angiography. The MCA flow velocities in this group ranged from 120 cm/sec to 230 cm/sec on the affected side(s). Angiograms from a 23 year old woman are shown in figure 1; she had two episodes of bleeding from an aneurysm of the anterior communicating artery 3 and 7 days prior to the investigation. The MCA's (and also the carotid siphons) were clearly spastic; and the patient also had bilateral spasm of the ACA's. Spectral displays of the signals from both MCA's are shown in figure 2, high frequencies heard from the Doppler audio output corresponded to pathological velocities of flow, 120 cm/sec on the right and 140 cm/sec on the left side (time-mean of maximum instantaneous velocity). The investigation of the ACA's (not shown) revealed flow velocities slightly lower (100 cm/sec right and 120 cm/sec left) than those in the MCA's. Two of the patients had moderate unilateral spasm of the ACA. In one case we found an elevated flow velocity in the contralateral ACA, unfortunately, the signals from the spastic ACA were too weak to be evaluated. The other case had a slightly elevated ACA flow velocity (60 cm/sec) on the spastic side, while the contralateral side was normal (48 cm/sec). Angiography revealed an excellent collateral capacity of the anterior communicating artery in both these cases; there was a strong cross-filling in the pericallosal arteries from the non-spastic side, while only weak filling was found through the spastic ACA.

290

Fig. 1

R. Aaslid, P. Huber and H. Nornes

Angiograms of a 23 year-old woman with two SAH's 3 and 7 days before. The right side is shown in a slightly obligue projection.

Discussion Angiography gives a detailed picture of the extent and severity of cerebro-vascular spasm; in contrast, the transcranial Doppler method detects a haemodynamic effect of arterial narrowing. We found a marked increase in the flow velocities through spastic arterial segments, in the spastic MCA the flow velocity was at least 4 standard deviations above the mean value in normal subjects. Our experience in the present series indicates that flow velocities between 120 and 200 cm/sec are associated with moderated spasm. Values above this range signal severe arterial narrowing which may become dangerous, particularly if there is a marked rising trend over the last day(s). However, no fixed classification can be made on the basis of valocities alone, the extension of the spasm, the cerebral perfusion pressure and possible oedema also influence the outcome. The situation is even more complicated in the ACA. This artery may channel collateral flows, or it may be circumvented. We do expect, however, that spasm which is hemodynamically dangerous will produce clearly elevated velocities due to high pressure gradients over severely narrowed segments in this artery; it is difficult to imagine a spasm causing significant loss of cerebral perfusion pressure without high velocities being invoked. A narrowed arterial lumen unfortunately also produces a

Noninvasive transcranial Doppler ultrasound recording in basal cerebral arteries

291

200 + MCA R

200 va 15fl F 0 >- 100 f-

MCA L

(.) CJ 50 . 1 III >•

0 -50 Fig. 2

Spectral displays of the Doppler signals from the middle cerebral arteries (R right side, L left side) in the same case that was shown in fig. 1. Note low frequency components symmetrically distributed around the baseline in systole. Abscissa is time (2 seconds shown).

weak Doppler signal, and it may sometimes be difficult to obtain signals from spastic ACA's. A relatively low frequency systolic murmur can be seen in figure 2. This is not a proper Doppler shift, it reflects the phenomenon of phase modulation of the ultrasonic echoes by vibrating anatomical structures; the spectral components from such murmurs are symmetrically distributed around the baseline of the spectral display [3]. The ultrasonic instrument operates in this mode as a highly sensitive focused microphone. Such sounds from spastic arteries were described by Olinger and Wasserman [8], they used conventional electronic sound amplification from sensitive microphones outside the skull. We found murmurs in all patients who had angiographically verified vasospasm, and also in those who developed high flow velocities (above 120 to 150 cm/sec). The bruit was strongest distal to a focal spasm, but in some cases we also detected a musical murmur of pure tone quality which seemed to be located near the region of highest velocities. On the spectral display this type of murmur was manifest as narrow bands symmetrical around the baseline; sometimes two or three higher harmonics were also seen [3]. Both these types of murmurs are probably caused by vortex formation in the spastic arteries, setting up vibrations in the surrounding structures [5]. Vortex formation (by some authors called turbulence) is associated with flow energy losses, and its presence indicates a pathological

R. Aaslid, P. Huber and H. Nornes

292

haemodynamic state. The intensity and the frequency of the murmurs may give some information on the severity of spasm. No such sound phenomenae were detected in the series of 5 0 normal subjects. The flow velocity in an arterial segment can be expressed mathematically as the volume flow rate divided by the cross-sectional area of the lumen. A determination of flow could therefore provide additional information, and the ideal combination would, indeed, be that of transcranial Doppler with regional CBF methods. We have not yet had the opportunity to conduct such a combined study; however, a simpler and not as specific approach was employed to assess changes in the CBF. The ICA in the neck is normally not affected by cerebral vasospasm after SAH, therefore, the assumption was made that relative changes in CBF could be monitored by recording the flow velocity in this artery. The use of 2 MHz pulsed Doppler facilitated insonation of the ICA at sharp angles, in this way we tried to minimize the errors due to day to day variations in the angle between the ultrasonic beam and the direction of flow. Figure 3 presents the results of combined ICA and MCA recordings plotted as trends in the case that was illustrated in figures 1 and 2. A first peak in the MCA flow velocity trend was found on day 8 (15 hours after angiography), this was paralleled by a similar peak in the ICA curve. A second peak in the MCA trend occurred on day 11, this time the ICA recording showed a slight decline. The flow velocities in the MCA's fell over the following days, the ICA showing a stable trend. This was inter300

250 - -

o

200 - -

H 150 +

RIGHT

t

100--!SAH I

S0--

t

SAH

I

A 4

O 4 ICA

LEFT

' 14

DAYS Fig. 3

> I 21

28

Time-courses of flow velocities in the middle cerebral arteries (MCA) and extracranial internal carotid arteries (ICA) from the case shown in figs. 1 and 2. SAH = episode of subarachnoid haemorrhage; A = time of angiography; O = time of operation.

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293

preted as release of vasospasm — or at least not further constriction — and the patient was operated on day 14, clipping the aneurysma. Postoperatively, a third peak in the M C A was observed on day 16, the ICA trend also demonstrated a marked increase. The patient had no neurological symptoms of the spasms during their occurrence. The first and the third peaks in the M C A flow velocities, being superimposed on gradually rising and falling trends respectively, seem to reflect temporary increases in CBF due to intervention — the ICA recordings give useful information for the interpretation of these phenomenae. The second peak, in contrast, probably corresponds to maximum arterial narrowing. The time-courses of combined ICA and M C A recording are shown and discussed for two other cases elsewhere.

Conclusion Cerebral vasospasm causes a significant increase in the flow velocity through the affected arterial segments; this effect can be measured by the described transcranial Doppler approach. The flow in spastic arteries is disturbed producing murmurs which can be detected together with the Doppler shifts. The ultrasonic investigation — being non-invasive — does not cause any additional discomfort to the patient — and permits monitoring of the onset and resolution of vasospasm in the individual case.

References [1] Aaslid, R., P. Huber and H. Nornes: Evaluation of cerebrovascular spasm with transcranial Doppler ultrasound. J. Neurosurg. 60 (1984). In press. [2] Aaslid, R., T. M. Markwalder and H. Nornes: Non-invasive transcranial Doppler ultrasound recording of flow velocity in basal cerebral arteries. J. Neurosurg. 57, 769-774 (1982). [3] Aaslid, R. and H. Nornes: Musical murmurs in human cerebral arteries after subarachnoid haemorrhage. J. Neurosurg. 60, (1984). In press. [4] Blaumanis, O. R., P. A. Grady and E. Nelson: Hemodynamic and morphologic aspects of cerebral vasospasm. In: T. R. Price, E. Nelson (eds): Cerebrovascular Diseases. Raven Press, New York 1979. [5] Bruns, D. L.: A general theory of the causes of murmurs in the cardiovascular system. Am. J. Med. 27, 3 6 0 - 3 7 4 (1959). [6] Nornes, H., A. Grip and P. Wikeby: Intraoperative evaluation of cerebral hemodynamics using directional Doppler technique. Part 2: Saccular aneurysms. J. Neurosurg. 50, 5 7 0 - 5 7 7 (1979). [7] Olinger, C. P. and J. F. Wasserman: Electronic stethoscope for detection of cerebral aneurysm, vasospasm and arterial disease. Surg. Neurol. 8, 2 9 8 - 3 1 2 (1977). [8] Spencer, M. P.: Hemodynamics of carotid artery stenosis. In: M. P. Spencer, J. M. Reid (eds): Cerebrovascular Evaluation with Doppler Ultrasound. Martinus Nijhoff, The Hague 1981.

Flow pattern studies during operation for aneurysm J. Gilsbach, A. Härders

Introduction Doppler sonographic studies of brain vessels during aneurysm operations have so far only been reported by Nornes et al. [4], These authors point out that vasospasms can be recognized from local flow acceleration. However, there are no systematic intraoperative studies on patients operated on within 72 hours after their last subarachnoidal haemorrhage. We have therefore re-evaluated 22 cases having had an early operation out of 60 intra-operative recordings made during aneurysm surgery, trying to establish which Doppler findings were typical and how they were to be interpreted.

Material and method The instrument used was a high resolution 20 M H z pulsed Doppler velocity meter with miniaturized probes [2]*. Whenever it was possible, the basal arteries and the aneurysm were recorded before clipping, or at the latest soon after the clips were in position. All of the stem arteries were examined and when ever possible other segments of the Circle of Willis as well. We evaluated mean frequency analogue curves, which were obtained with a zero-crosser and polaroid-documented frequency spectra from a real time frequency analyzer. The operations were performed under neuroleptanaesthesia with normotension, normothermia, and normocapnia. Only in the case of a premature aneurysmal rupture or an extremely difficult operation a short term artificial hypotension with sodium nitroprusside was applied.

* MF 20 Fa. Eden.

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Results Among 31 aneurysm cases operated on within 1 to 7 weeks following a subarachnoidal haemorrhage and showing no symptoms, 35% (11) showed normal flow patterns, 65% (20) had spasms in at least one vessel, which could be recognized from a locally increased flow velocity with irregular pulse curves, while 7 patients with no previous bleeding all had normal findings (tab. 1). Twenty-two patients were operated on within 72 hours. 36% (8) had normal flow patterns and 14% (3) had local accelerations in at least one vessel (fig. 1). These accelerations decreased only insignificantly, if at all, when topical vasodilators were applied locally. Lumen reductions were not clearly recognizable externally. However, they could be proved angiographically as well as by Doppler sonography. Apart from locally raised flow velocity and irregular pulse curves with small amplitudes, the flow profiles in the stenosed areas indicated the difference between these spastic and normal vessels. 50% (11) had flow patterns that deviated from the norm but did not correspond to vasospasm curves. The mean Doppler frequencies were 20% to 60% higher than the

1sec Fig. 1

Flow patterns of the middle cerebral artery with its branches seven weeks after the aneurysm had ruptured. Note the high flow velocites in the region of the spasm; the reduced proximal velocity indicates a haemodynamically effective lumen reduction.

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average values found among normal adults. The pulse amplitude was very small, and not localized but could be recorded on multiple vessels and regions of the side of the approach or bilaterally (fig. 2). These findings were usually obtained when there was severe bleeding.

Discussion and Summary Vasospasms do not normally occur until the third day following a subarachnoidal haemorrhage. Should vasospasms occur during this early stage, it is probable that an additional previous bleeding took place. This was the case in 3 of our patients which were operated within 48 hours after the last bleeding. They had bleeds 13 to 28 days before the most recent haemorrhage. The causes of decreasing resistance with consecutive flow acceleration in normal size or wide vessels, registered by Doppler sonography, are unknown. The intracranial pressure reduction caused by the trepanation, suction of the liquor or the mechanical irritation caused by the operation could be explanations. It is also feasible that a

Fig. 2

Flow patterns of the anterior cerebral arteries 48 hours after a subarachnoidal bleeding from a ruptured anterior communicating aneurysm. Note the generally high flow velocites with irregular pulse curves.

298 Table 1

J. Gilsbach and A. Härders Intracranial, intra-operative Doppler findings in aneurysm operations (spastic: local acceleration due to narrowing of the basal arteries; hyperaemic: general acceleration due to a reduction of vascular resistance

flow patterns in aneurysm surgery normal

spastic

hyperaemic

acute operations (n = 22) delayed operations (n = 31) without SAH (n = 7)

8 ( 36%)

3 (14%)

11 ( 35%)

20 (65%)

7 (100%)

-

11 (50%) 0 —

pre-operatively existing vaso-dilatation occurs in the acute phase, as Fox and Ko [1] deduced from angiograms of wide vessels, however no comparable findings on cerebral blood flow are available. Extensive application of Doppler-sonography might providea rational explanation [3].

References [1] Fox, J. L. and J. Ko: Cerebral vasospasm: a clinical observation. Surg. Neurol. 10, 269—275 (1978). [2] Gilsbach, J.: Intraoperative Doppler Sonography in Neurosurgery. Wien/New York: Springer-Verlag 1982. [3] Härders, A. and J. Gilsbach: Angiospasm after aneurysm surgery in the acute stage. Transcranial Doppler ultrasound findings. In this volume, pp. 299-302. [4] Nornes, H., A. Grip and P. Wikeby: Intraoperative evaluation of cerebral hemodynamics using directional Doppler technique. Part 2: Saccular aneurysms. J. Neurosurg. 50, 8 7 0 - 5 7 7 (1979).

Angiospasms after aneurysm surgery in the acute stage. Transcranial Doppler ultrasound findings A. Härders, J . Gilsbach

Introduction The 2 MHz pulsed Doppler technique developed by Aaslid has made it possible for the first time to detect transcranially the flow patterns in the circle of Willis [1, 2]. The evaluation of cerebral spasms following subarachnoid haemorrhages has until now not been possible without angiography. The first transcranial Doppler recordings following acute aneurysm operations are presented. The extent to which these findings can explain the clinical course and which therapeutic consequences can be deduced is discussed.

Material and methods Eight patients who were operated on within 48 hours after SAH were controlled with transcranial Doppler sonography (TC 2—64 Transcranial Doppler, Eden Med. Elektronik). The patients were treated with nimodipine [4]. Doppler sonographic examinations were carried out transtemporally on the middle cerebral artery and the internal carotid artery, and transorbitally on the carotid siphon. The Doppler frequency spectrum of the 2 MHz device was recorded on a real time frequency analyzer (Angioscan, Unigon Industries Inc.). Flow direction was determined by means of a flow adaptor (TRA 1, Unigon Industries Inc.). The peak systolic and the end diastolic frequency as well as the time average mean can be determined with the Angioscan. Flow velocity was calculated as follows : v = 0.039 x f [1],

Results Neither angiography nor Doppler sonography could detect spasms among the 8 patients who were operated on within 48 hours following SAH. Two patients, who pre-operatively had had only slight headaches and neck stiffness and who in C T showed only a small amount of blood in the basal cisterns, showed post-operatively

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normal flow velocities in the MCA, ICA and carotid siphon. On the fourth day after the operation one patient showed increased flow velocity (120 cm/sec) on the right side and clinically intensified headache and somnolence. After 7 days the velocities had returned to normal. One patient, who had become soporose on the first day after the operation, showed normal time average mean velocities. However, the frequency spectrum indicated an increase in intracranial resistance. Lumbar puncture revealed a pressure of 320 mm H 2 O. In the remaining 4 patients, we found local unilateral (MCA-ICA) and /or bilaterally pathological high velocity increases. Aaslid [2] reported that vessels with flow velocities higher than 120 cm/sec show a vasospasm in the angiogram. These 4 patients, who developed transient hemiparesis, had such spasm velocities in the ICA and MCA on the side of the operative approach. The highest velocity measured in an MCA was 190 cm/sec. When the Doppler shifts were above half of the pulse repitition the "aliasing" effect was observed [5]. The newer TC2-64 has a built-in microcomputer which eliminates this.

Fig. 1

63 year old female, 11th day after SAH: spasm velocity in the right MCA (with aliasing), right ICA and left MCA and ICA shows slightly increased velocites.

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Three patients with a local vasospasm in the MCA showed increased flow velocity in the contralateral MCA and ICA, which, however, was below the spasm velocity (75-100 cm/sec) (fig. 1). One patient developed a hydrocephalus malresorptivus. The right MCA was spastic and the left MCA on the 21st day showed sins of increased resistance. The ICP was 170 mm H2O (fig. 2). In 2 patients with spastic MCA's, we were able to hear musical murmurs in the Doppler spectrum. This was a result of periodic vibration of the arterial wall [3].

Discussion With the 2 M H z pulsed Doppler velocity meter we are able to detect changes in blood flow velocity as a result of reductions in vessel diameter. Two out of 8 patients showed normal flow patterns following aneurysm surgery in the acute stage and after treatment with nimodipine. Why the 4 patients who had spasm velocities on the side of the operative approach developed a paresis remains unanswered. CT showed

1sec Fig. 2

Same case as in fig. 1: left MCA developed from the 4th to the 21st day after SAH an increased intracranial resistance. The Doppler spectrum changed from internal to external type (IR 0.75).

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in all patients a severe subarachnoidal haemorrhage. A mechanical cause, triggered off by the opening of the Sylvian fissure, is unlikely, since the spasms occurred days after the operation and the remaining 4 patients developed no spasms. Why 3 patients, who in addition to the spasm in the other vessels, showed increased flow velocity between 75 and 100 cm/sec cannot be clarified in the small number of cases. It could be that a slight generalized lumen reduction or a flow acceleration caused by reduced resistance, were instrumental for this increase. The local spasm was treated with hypervolaemia and hypertension; increased intracranial pressure was treated with hypovolaemia and dehydration with Mannitol after a hydrocephalus malresorptivus was ruled out by CT. The development of spasm can be followed by repeated Doppler sonographic transcranial controls of the circle of Willis after SAH. Flow velocity not exceeding 120 cm/sec, caused no neurological deficits in patients.

References [1] Aaslid, R., T . - M . Markwalder and H . Nornes: Non-invasive transcranial doppler ultrasound recording of flow velocity in basal cerebral arteries. J. Neurosurg. 5 7 , 769—774 ( 1 9 8 2 ) . [2] Aaslid, R., P. Huber and H . Nornes: Evaluation of cerebro-vascular spasm with transcranial doppler ultrasound. J. Neurosurg. (in press). [3] Aaslid, R. and H . Nornes: Musical murmurs in human cerebral arteries after subarachnoid haemorrhage. J. Neurosurg. (in press). [4] Allen, G. S. et al.: Cerebral arterial spasm - a controlled trial of Nimodipine in patients with subarachnoid haemorrhage. N e w England Journal of Medicine 3 0 8 , 6 1 9 - 6 2 4 ( 1 9 8 3 ) . [5] Hartley, C. J . : Resolution of frequency Aliases in ultrasonic pulsed Doppler velocimeters. I E E E Transactions on Sonics and Ultrasonics 2 8 , 6 9 - 7 5 ( 1 9 8 1 ) .

The ultra short-lived isotope 195mAu — a new diagnostic tool in quantitative cerebral blood flow measurements P. Lindner, O. Nickel, K. Hahn, D. Eifiner

Introduction and methods The new short life time isotope 195 m Aurum has some suitable features. The halflife of Aurum 195 m is 30.5 seconds. The rate of generation of Aurum 195 m is rapid so that within 2 minutes more than 98 per cent of the theoretical maximum has been formed. Since the decay of Aurum 195 m is also fast an injection can be repeated after 3 minutes (6 half-lifes) without any need for background subtraction and with the same specific activity. The calculated whole body radiation dose after 3 successive administration of 25 mCi Au 195 m amounts 50 mrad. In comparison to a Technetium 99 pertechnetate injection it is estimated that the dose to the patients is reduced by a factor of eight [1]. We have measured a gamma-camera energy spectrum of a 195 m-Au generator eluate immediately after elution. We have found two peaks, one at a energy level of 262 KeV and a second at 68—70 KeV. The half-life time of both energy lines are nearly equal and lies in the range of 30 sec. Both peakes can be used for imaging and perfusion studies. Details are described in Nickel [7]. Both strong energy lines of the isotope 195 m Au energy spectrum allow to make successive quantitative measurements not only in p.a. projection but also in lateral views of the hemispheres within minutes. The time interval between two successive measurements is at least 3 minutes. In the case of p.a. positions one should use the high energy peak of 262 KeV, whereas for lateral views of the hemispheres the low energy peak (69 KeV) is ideal because no significant "look-through" effect is detected. The half value thickness for the absorption of 68KeV photons in water is about 4 cm. At least the possible "look-through" is diminished in comparison to the Xenon photon energy of 85 KeV. The advantage of a heart rate dependent recirculation correction limits the detection time to 20—40 sec. Further details and features of the 195 m Au generator are described in Nickel [7], Lindner [3, 4, 5], Schad [8].

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Clinical investigations and results With the use of a multicrystal camera, which allows to measure high count-rates with high sensitivity, we made our investigations in the following way: T h e patient is sitting before the camera either in posterior anterior position or in lateral position. After eluating 2 ml we inject immediately into the cubital vein, followed by a handinjected flush of 2 0 ml saline. A serial scintigram with 2 frames per second is generated over a detection time of 5 0 sec. The investigation can be repeated after at least 3 minutes in the same or any other position. In routine we make 3 injections, one in p.a. position (262 KeV) and 2 in both lateral views (68 KeV). The interval of at least 3 minutes correspond to 6 half lives so that no background correction is necessary. The data are corrected for homogenity and for the decay of 195 m Au. The data can than be evaluated by a computer program which computes quantitative cerebral blood flow values over selected regions of interest, following the above mentioned theoretical concept. It is also possible to generate parametric images, which show the regional speed of inflow of the bolus, the distribution of reverse regional mean transit times and a quantitative mapping of regional cerebral blood flow. The use of a multicrystal camera gives as high count rates with 195 m Au as with a bolus of 15—20 mCi 9 9 m Technetium, so that images with low noise and with a spatial resolution in the order of 1—2 cm can be generated. By this technique we study routinly all cerebro-vascular diseases, especially all patients with stroke. In order to demonstrate the effectivity of the reported method the figure 1 shows the quantitative mapping of cerebral blood flow from a patient with an angiographically proven stenosis of the left internal carotid artery. T h e region of the occluded vessel is clearly seen, no significant "look through" effect can be recognized. The regional cerebral blood flow values are quantified in a scale besides the pictures. The integrated values over both hemispheres seperately are: right hemispheres: 3 8 . 5 ml/min/100 g; left hemispheres: 4 4 . 8 ml/min/100 g. (Normal value: 4 5 ml/min/100 g ± 5 % . ) We have been very interested in examining the method in mental stimulation exercises with volunteers in the same way as reported by many authors.

Stimulation exercise A simple mental stimulation test can be made. A volunteer sits before the camera with closed eyes at rest for 2 - 3 minutes in left lateral position. A bolus injection is made as described when the volunteer has his eyes closed. In the same position the investigation is repeated after 3 minutes. The patient has opened his eyes and is fixing a moving object in front of his eyes during the second investigation. For both inves-

T h e ultra short-lived isotope 195m A u - a n e w diagnostic tool

Fig. 1

305

P a r a m e t r i c images of regional cerebral blood flow. Posterior view a n d gray scale with gray levels c o r r e s p o n d i n g to RCBF values f r o m 15 to 60 ml/min • 100 g. This image results f r o m a p e r f u s i o n study d o n e with the 2 6 2 KeV g a m m a line. T h e f l o w is significantly diminished in the left hemisphere due t o an occlusion of the left carotid artery.

tigations the quantitative mapping of regional cerebral blood flow is calculated. Then the study in rest is subtracted from the study during mental activation of the areas of optical perception. As seen in figure 2 there is a significant change in cerebral blood flow pattern. The average increase during stimulation in the area of optical perception has been 11.5% and regionally up to 30%. The increase of CBF in cerebral regions responsible for movement (the prae- and postcentral gyrus) has been: 6.2%. Figure 2 shows the regional CBF differences with a regional maximum of increase over the visual perception center in the cortex of the occipital lobe. Local changes in the motion activation center can be seen (the area of the middle cerebral artery or the prae- and postcentral gyrus respectively). Finally figure 2 shows the mean regional CBF changes of 8 volunteers (mean age: 49.3 y; youngest 20 y, eldest 73 y) who have been investigated by the described stimulation

306

Fig. 2

P. Lindner, O. Nickel, K. Hahn and D. Eissner

Change of RCBF-pattern during visual stimulation. The mean percentual change of RCBF is shown from left lateral views of 8 volunteers. The gray levels are in the range 1 - 1 0 % change. The maximum change of about 10% is in the visual cortical center.

exercise. This results are in excellent agreement with stimulation exercises made by Lassen [2]. Figure 2 shows clearly the increase of CBF during stimulation in the optic and movement centers of the brain.

Discussion The results demonstrate the high sensitivity of the method. The spatial resolution is 1—2 cm approximately. Most of Xenon clearance techniques use 16 single detectors for each hemisphere. The presented technique using a multicrystal camera (Baird Atomic) uses about 100—120 single crystals for generating parametric images for lateral views of the hemispheres. For p.a. projections the average quantitative cerebral blood flow value for a hemisphere is calculated with 15 to 30 single crystals in dependance of the seizure of the region of interest. Obviously the spatial resolution of the parametric images, especially for the blood flow patterns is much better when compared to Xenon clearance techniques. Simple mental stimulation can be detected and quantified in relation to regional blood flow changes within 5—10%. The results prove primarily that the quantitative measurement of regional blood flow patterns is not only possible with freely diffusible Xenon but also with non-diffusible radiotracers like 195 m Aurum in combination with the quantitative evaluation method described by Lindner [ 3 , 4 , 5 , 7]. N o doubt this is the ideal isotope for clinical investigations of cerebro-vascular disease [4, 5].

The ultra short-lived isotope 195m Au - a new diagnostic tool

307

Summary A previously reported method for quantitative cerebral blood flow measurement for non-diffusible radiotracers [3, 4] has been applied on patients after a stroke and on volunteers undergoing a mental stimulation exercise. Quantitative measurements of cerebral blood flow patterns are possible not only in posterior-anterior but also in lateral views of the brain, when using the recently developed generator for the short lived (30 sec) isotope Au-195 m [5]. The energy spectrum of the eluate of the generator shows two strong photon peaks, one at an energy level of 68 KeV and a second at an energy-level of 2 6 2 KeV. The low energy peak is suitable for perfusion studies in lateral views of the hemispheres, no "look through" effect is seen. The high energy level is most suitable for studies in posterior-anterior positions. The studies last less than 1 minute and can be repeated after 3 minutes. Parametric images for quantitative regional cerebral blood flow can be generated. In the case of a stroke the area of occluded vessels can be detected. Quantitative activation patterns of cerebral blood flow during mental stimulation can be visualised. The results prove that not only with freely diffusible indicators like Xenon but also with non-diffusible indicators quantitatively cerebral blood flow patterns are measurable.

References [1] Garcia, E., J . Mena and R. de Jong: Gold Au 195 m, short lived migle photon emitter for haemodynamic studies. J . Nucl. Med. 2 2 , 71 (1981). [2] Lassen, N. A. and D. H. Ingvar: Regional cerebral blood flow measurements in man. Archs. Neurol. Psychia (Chicago), 6 1 5 - 6 2 2 (1963). [3] Lindner, P., F. Wolf and N. Schad: Assessment of regional blood flow by intravenous injection of 9 9 m Technetium Pertechnetate. Europ. J . Nucl. Med. 5, 2 2 9 - 2 3 5 (1980). [4] Lindner, P.: Quantitative, noninvasive cerebral blood flow measurements with nondiffusible tracers using a heartrate dependent recirculation correction, application in carotid surgery. Accepted for publication in Europ. J . Nucl. Med. (1983). [5] Lindner, P. and O. Nickel: Quantitative activation patters of cerebral blood flow during mental stimulation after intravenous injection of 195 m Aurum. Neuroradiology 2 5 , No 3 (1983). [6] Meier, P. and K. L. Zierler: On the theory of the indicatordilution method for measurement of blood flow and volume. J . appl. Physiol. 6, 7 3 1 - 7 4 3 (1954). [7] Nickel, O., P. Lindner and N. Schad: Parametric imaging of cerebral blood flow with the short lived isotope Au 195 m. Accepted for publication in Europ. J . Nucl. Med. (1983). [8] Schad, N., H. Schon, O. Nickel, H. O. Le-Thi and P. Lindner: Aurum 195 m: Application in first pass cardiac examinations. T o be published in J . Nucl. Med. (1983). [9] Zierler, K. L.: Equations for measuring blood flow by external monitoring of radioisotopes. Circulation Res. 16, 3 0 6 - 3 2 1 (1965).

Influence of stenotic/occlusive lesions of cerebral arteries and subarachnoidal haemorrhage on lactate and glucose content in lumbar cerebrospinal fluid

(CSF)

T. O. Kleine, A. Lütcke

Introduction Occurrence of vasospasms has been observed frequently during the first days after a subarachnoidal haemorrhage (cf. [4]); these spasms arise probably by contractions of smooth muscle cells from the tunica media of cerebral arteries producing permanent arterial stenosis [5] and long lasting vasospasms can cause cerebral infarction [6]. However, the patho-biochemical mechanisms of vasospasm remain unclear: Some humoral and mechanical factors have been discussed (cf. [4]) as well as metabolic factors, e.g. hypothermia and overventilation [1]. In the present study we have measured lactate and glucose content in the lumbar CFS of 21 selected patients who had vasospasms and other stenotic or occlusive lesions of cerebral arteries with and without subarachnoidal haemorrhage.

Methods Computed tomography (CT) was performed with Somatom DR 3 from Siemens, Erlangen. Angiography of cerebral arteries was carried out by catheterization via femoral or subclavian artery or retrograde brachial angiography and direct puncture of the carotid artery as well as using the Siemens equipment.

Lumbar puncture procedure and analysis of CSF CSF samples of 1—3 ml were obtained in several portions from lumbar region of all patients at the same day, where CT or angiographic investigations were performed. Samples were analysed for cell count (erythrocytes and leucocytes), and total protein [3]. Lactate and glucose were measured enzymatically [2, 3] in native samples within 3 h after collection or the samples were kept frozen at —20 °C.

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Patients Controls CSF was collected from 20 patients, 7 females and 13 males (ages 15 to 63 years, median 41) undergoing CT investigation. CT findings of subarachnoid spaces, ventricles, sulci and brain density were of normal ranges. In CSF samples leucocyte and erythrocyte counts were found to be 5/^1 and 200/^1, respectively, and total protein between 20 to 40 mg/dl. Patients with subarachnoid haemorrhage CT and angiographic findings of 4 female and 6 male patients (ages 22 to 80 years, median 54) are listed with numbers 1 to 10 as follows: No. 1: 22-year-old woman showing extra-vasated blood in all subarachnoid spaces, thrombosed aneurysm in carotid artery bifurcation, and low-density zone with some compression of frontal ventricular horn. No. 2: 41-year-old woman showing extra-vasated blood in all subarachnoid and ventricle spaces. No. 3: 48-year-old man showing extra-vasated blood mainly in basal cisterns, and thrombosed internal carotid artery aneurysm with basal low-density zones. Haemorrhage has been absorbed 3 weeks later. No. 4: 53-year-old man showing subarachnoid haemorrhage and one week later vasospasms with internal carotid and circle of Willis arteries. No. 5: 55-year-old woman showing extra-vasated blood in interhemispheric fissure and in suprasellar cistern and from the anterior communicating artery an aneurysm with local spasms of one week duration. No. 6: 57-year-old man showing anterior communicating artery aneurysm with wide-spread vasospasms, and subarachnoid haemorrhage. No. 7: 59-year-old man showing subdural haematoma over one hemisphere with ventricular compression and rupture into subarachnoidal space. No. 8: 61-year-old man showing extra-vasated blood over both hemispheres, small aneurysm with wide-spread vasospasms of the middle and anterior cerebral arteries with partial infarction of the island of Reil. No. 9: 80-year-old woman showing extra-vasated blood in ventricles and basal cisterns, over cerebral and cerebellar hemispheres with partial infarction in both cerebral hemispheres. No. 10: 53-year-old man showing extra-vasated coagulated blood in basal cisterns and ventricles.

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Patients with cerebro-vascular stenotic and occlusive lesions without subarachnoid haemorrhage Angiographic and CT findings of 9 female and 2 male patients (ages 40 to 80 years, median 57) are listed with numbers 11 to 21 as follows: No. 11: 40-year-old man showing low-density zones within area of internal capsule due to infarction of middle cerebral artery one week before. No. 12: 46-year-old woman showing low-density zone within one island of Reil due to middle cerebral artery infarction one week before. No. 13: 47-year-old woman showing low-density zone within frontal medullary zone due to middle cerebral artery infarction > 3 days before. No. 14: 52-year-old woman showing carotid artery stenosis. No. 15: 55-year-old man showing anterior communicating artery aneurysm with wide-spread vasospasms and low-density zone fronto-parasagittal due to infarction 5 days before. No. 16: 57-year-old woman showing middle cerebral artery infarction 4 weeks before. No. 17: 63-year-old woman showing severe stenosis of anterior and posterior communicating artery. No. 18: 64-year-old woman showing multiple severe stenosis of arteries of circle of Willis. No. 19: 64-year-old woman showing infarction CT undetectable. No. 20: 71-year-old woman showing old infarction within internal capsule and both hemispheres. No. 21: 80-year-old woman showing parasagittal low-density zones with cortical blood suffusions.

Results Controls Lactate concentrations in the control group (n = 20) ranged from 8.7 to 16.2 (mean 12.6) mg/dl. These values correspond to earlier findings [2, 3] with up to 50-year-old patients; 51- to 75-year-old control persons had an upper limit of 23.4 mg/dl [2, 3]. Glucose levels in the same control group (n = 20) ranged from 54 to 84 (mean 67) mg/dl. These values are slightly higher than earlier findings [2, 3] with 5-to 89year-old patients having a blood glucose level of normal range.

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Subarachnoidal haemorrhage CSF of all 10 patients was xanthochrom and had increased contents of erythrocytes, protein, and lactate (fig. 1). The mean value of lactate (32.0 mg/dl) exceeded that of controls by factor 2.5. The mean value of glucose (53 mg/dl) was lower than that of controls by factor 1.3. The difference was significant for lactate (p < 0.001) and glucose (p < 0.02; Student's t-test). A positive correlation was found between lactate content and erythrocyte counts (p < 0.01; t-test) as well as between lactate and protein content (p < 0.05) (fig. 1). This was not true for glucose content (r = 0.3 and 0.1, respectively; 3 patients had elevated blood glucose levels).

Cerebro-vascular stenotic and occlusive lesions without subarachnoidal haemorrhage CSF of 11 patients had erythrocyte counts up to 832/|uil and leucocyte counts up to 363/(xl. Protein content increased to 280 mg/dl. Glucose content ranged from 43 to 92 (mean 66) mg/dl and lactate content from 7.6 to 33.3 (mean 16.5) mg/dl. Comparing with controls the differences were not significant. There was no correlation between lactate and protein content (r = 0.1) nor between glucose and protein content (r = 0.1).

Discussion Of the 9 patients suffering from recent subarachnoidal haemorrhage 6 revealed elevated lactate concentrations (fig. 1) and 4 diminished glucose contents in CSF. With 2 patients (No. 3 , 4 ) a further investigation yielded lactate and glucose contents of normal range one and 3 weeks later (fig. 1). With one patient (No. 5) who had had an ictus one week before, lactate and glucose contents were in normal range. These findings indicate that elevated lactate content and diminished glucose concentration appear to occur only in the acute state of subarachnoidal haemorrhage and return to normal levels during the subacute state. Two subgroups can be distinguished in patients suffering from subarachnoidal haemorrhage: One subgroup developing complications such as vasospasms and infarction, or both (No. 1, 3, 4, 6, 8, 9) had elevated lactate content ( > 25 mg/dl) in all cases (fig. 1) and diminished glucose content in 4 cases. In the other subgroup without complications (No. 2, 7, 10) only two patients showed slightly elevated lactate contents (fig. 1). CT findings of one patient (No. 10) whose glucose level was diminished to 38 mg/dl, indicated coagulated blood in the ventricles. This might have reduced the transport of ventricle fluid (rich in glucose) to lumbar CSF. However, there was no correlation between glucose content and erythrocyte counts or protein content in the samples. Considering erythrocyte number and protein content of CSF

313

Influence of stenotic/occlusive lesions of cerebral arteries and subarachnoidal haemorrhage

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NG/DL

900

Correlation between lactate content (y) and erythrocyte counts (x in fig. 1 a) or protein content (x in fig. 1 b) in lumbar CSF of 9 patients (No. 1 - 9 ) suffering from subarachnoidal haemorrhage. Dashed line represents upper lactate limit. • patients with vasospasms in acute state; 0 patients without vasospasms, but infarction or without complications in acute state; A and O patients in subacute state. fig. 1 a: y = 19.2 + 0.000092 x ; r = 0.77 ; p < 0.01. fig. 1 b: y = 16.8 + 0.04 x ; r = 0.73 ; p A 0.05.

314

T. O. Kleine and A. Liitcke

samples as parameters of blood contamination there is a significant positive correlation between lactate content and both the parameters (fig. 1). However, there was no correlation between blood expansion into subarachnoid and ventricle spaces and lactate content in lumbar CSF. Rather high lactate levels were observed in CSF together with vasospasms and infarction or both (fig. 1). Moreover, lumbar CSF lactate content of normal range was found during acute and subacute state of cerebral artery infarctions (No. 11—13, 15, 16, 19—21). Two patients (No. 17, 18) suffering from severe stenosis of multiple cerebral arteries had elevated lactate contents ( > 25 mg/dl), but glucose contents were of normal range.

Summary Our findings indicate a high incidence between elevated lactate content in lumbar CSF ( > 25 mg/dl) and the event of vasospasms or severe stenosis of multiple cerebral arteries only during the acute state. But glucose content was seldom diminished. The significance and interrelation of elevated lactate level in cases of vasospasms of cerebral arteries has still to be elucitated.

References [1] Allcock, J . M . : Arterial spasm in subarachnoid haemorrhage. Acta radiol. Diagn. 5, 73—83 (1966). [2] Kleine, T. O.: N e u e Labormethoden für die Liquordiagnostik. Thieme Verlag, Stuttgart 1980. [3] Kleine, T. O.: Liquor. In: L a b o r und Diagnose (Hrsg. L. Thomas) 2. Auflage. M e d . Verlagsgesellschaft, M a r b u r g / L . 1983. [4] Krayenbühl, H., M . G. Yasagril und P. Huber: Zerebrale Angiographie für Klinik und Praxis. Thieme Verlag, Stuttgart 1 9 7 9 . [5] Mizukami, K., H . Kin, S. Araki, H . Mihara and Y. Yoshida: Is angiographic spasm real spasm? Acta neurochir. (Wien) 34, 2 4 7 - 2 5 9 (1976). [6] Sundt, T. M . , J . Szurszewski and F. W. Sharbrough: Physiological considerations important for the management of vasospasm. Surg. Neurol. 7, 259—268 (1977).

Determination of regional glucose metabolism in patients with ischaemic infarct by positron emission tomography K. Herholz, G. Pawlik, R. Wagner, K. Wienhard, W.-D. Heiss

Introduction Using ( 18 F)-2-fluoro-2-deoxyglucose (FDG) [11] in the deoxyglucose method developed by Sokoloff et al. [12] for autoradiographic determination of regional cerebral glucose metabolism made similar studies in man possible by means of positron emission tomography (PET). Since than a substancial number of investigations have been performed in normal volunteers during physiologic stimulation and in patients suffering from various diseases (review in [5, 10]). This contribution focuses on the topographical distribution of functional cerebral deactivation in patients with focal ischaemic lesions. Distant effects of local brainlesions on glucose metabolism or oxygen uptake in areas without structural damage in X-ray computed tomography (XCT) have been described [1, 7, 8], but definite relations to either localization and extent of the morphological lesion, or to the neurological deficit, have not been established.

Principles of metabolic model and tracer detection According to the principles of the model [12] glucose and deoxyglucose use the same carrier system for facilitated diffusion into the brain tissue and the same enzymatic reaction (hexokinase) for the first metabolic step of phosphorylation. However, due to the alteration at position 2 of the molecule D G cannot be converted into fructose6-phoshate and then further metabolized to CO2 and H2O, but is trapped in the cell because phosphate activity in brain tissue is very low. The resulting accumulation makes the compound well suited for tracer kinetic studies if an appropriate radiolabel is used. Individual steps of D G turnover can be represented in a three-compartment model, with kinetic constants ki and k2 for transport into and out of the cell and rate constant k3 for phosphorylation [12]. A fourth constant k4 is required only for recordings of longer duration (more than 45 to 60 min after tracer injection) because

316

K. Herholz, G. Pawlik, R. Wagner, K. Wienhard and W.-D. Heiss

only after that period of time dephosphorylation begins to play a significant role [9]. The mathematical model can be described by a complex integral equation in which individual expressions represent various measurable quantities or pools of metabolic constituents CMRG1 =

—^ LC

X

Ab

C(18F): total activity of label in the tissue is measured directly; C( 18 FDG): the precursor pool of unmetabolized DG in the tissue is calculated from the individual plasma curve and from kinetic constants previously determined in standard experiments, the difference between these two expressions yields the amount of metabolite, i.e. the DG-6-phosphate produced from time 0 to T; Ab: the integrated precursor activity supplied to the brain which equals the integrated plasma specific activity corrected for the lag in equilibration between plasma and tissue, the quotient of the metabolized product and precursor supplied being a measure of the relative amount of phosphorylated DG, i.e. the rate of DG metabolism. The latter value multiplied by plasma glucose concentration C(G1) yields the metabolic rate of glucose CMRG1. However, DG is extracted not exactly at the same rate as glucose and, therefore, the value must be corrected by a lumped constant LC, which is defined by a complex expression, and has also been determined in standard experiments. Errors caused by marked deviation of kinetic constants in pathologic tissue can be minimized by a dynamic approach: tissue activity is measured at short intervals from tracer injection until a steady state is reached between tissue and plasma DG. While the original method [12] used (14C)-2-deoxyglucose for autoradiographic determination of regional glucose metabolism in animal experiments, use of a positron emitting isotope, e.g. 18F, as this label offers several important advantages, also when compared with tracers decaying by single photon emission. Positrons travel only a short distance in tissue, then they combine with an electron and both annihilate emitting photons in opposite direction, both having the same energy of 511 keV. Recording of these coincident gamma quanta with two connected detectors permits to assign the event to the region between the two detectors. Due to the high and identical energy of the two photons detection, probability is almost independent from where in between any paired detectors the event occurred, and electronic collimation can be used in the design of detector systems providing high detection efficiency and accurate attenuation correction is available. From moving of steady multidetector arrays or rings large numbers of projections are obtained at different angles, and local activity distribution is reconstructed in cross-sectional images.

Determination of regional glucose metabolism in patients with ischaemic infarct

317

Procedure of investigations Studies reported here were performed in 22 patients with a recent ischaemic stroke documented by XCT. All subjects rested on a reclining chair in a room with low ambient light and noise, eyes closed and ears unplugged. Approximately 15 min before the start of recordings short catheters were placed into one cubital vein for injection and into a vein of the contralateral heated hand for blood sampling. FDG was synthesized according to a modification of the method of Ido et al. [6]. Approximately 5 mCi of FDG in normal saline solution were injected intravenously. Blood was sampled and plasma glucose as well as FDG concentrations were determined as described by Phelps et al. [9]. Seven equally spaced parallel planes, from the canthomeatal line (CML) up to 81 mm above, were simultaneously scanned with a four-ring positron camera (Scanditronix PC 384) at a spatial resolution of approximately 8 mm full width at half-maximum in 11 mm slices [4]. Recordings were taken at consecutive intervals increasing from 1 to 5 min during a period of 40 min, starting at FDG injection. Data from the tomographic device and from a sample changer used for plasma counting, as well as plasma glucose values, were stored in the memory of a VAX 11/780 (DEC) computer for later processing. Following decay correction the activity distribution in the scanned slices was reconstructed using an edge finding algorithm to determine the skull contour for attenuation correction [3], a deconvolution for subtraction of the scattered radiation [2], and a filtered back-projection algorithm. Static images recorded between 30 and 50 min after FDG injection were transformed into metabolic maps (fig. 1) employing a model that incorporates the slow hydrolysis of FDG-6-phosphate to FDG [9]. From the latter images slices could be reconstructed at any thickness and angle of cut for optimum visualization of points of interest.

Results Characteristic distant effects of focal ischaemic lesions of selected non-ischaemic brain regions in patients with typical infarction in the supply territory of the middle cerebral artery (fig. 2) are demonstrated in table 1. Metabolic changes were most severe in the infarct area proper, but glucose consumption was also significantly decreased in the other ipsilateral cortex and subcortical gray matter as well as in the contralateral cerebellum. Detailed analysis of another series of stroke patients with rather small infarcts in various brain regions provided some insight into the topographical nature of remote deactivation. Patients with cortical or subcortical lesions, and a neurologic deficit

318

Fig.l

K. Herholz, G. Pawlik, R. Wagner, K. Wienhard and W.-D. Heiss

Metabolic maps (9 slices from 0 to 98 mm above the orbito-meatal line, left brain side corresponding to right image side) of a normal volunteer. Local metabolic rates of glucose in (unol/100 g tissue/min can be read by comparing the gray of a region with the reference scale on the right.

Determination of regional glucose metabolism in patients with ischaemic infarct

319

1 - 17 - 21

- 25 - 28

- 32 - 36

Fig. 2

Metabolic maps (same arrangement as in fig. 1) of a patient with an ischaemic infarction in the left fronto-temporal cortex. Deactivation of the whole left hemisphere including basal ganglia and thalamus and the contralateral cerebellar hemisphere.

320

K. Herholz, G. Pawlik, R. Wagner, K. Wienhard and W.-D. Heiss

Table 1

r C M R G l c (nmol/100g/min) in various brain regions of patients with an ischaemic stroke

n

rCMRGlc ((j.mol/100 g/min, mean ± standard deviation)

sign test

ipsilateral

contralateral

P
3 "T3 öTD 'E & ^ g-S" a> ^ 28

time ( d a y s )

Incidence of vasospasm and type of spasm in relation of last SAH in 106 patients of group B.

Location of aneurysm and vasospasm The group B contained 3 9 aneurysms of the anterior communicating artery, 31 of the internal carotid artery, 2 2 of middle cerebral and 8 of the anterior cerebral. The remaining 11 aneurysms stem from the basilary artery and other vessels, occasionally multiple aneurysms occurred. Vasospasm was caused by all ruptured aneurysms in the region of the cerebri media (55%), of the anterior communicating artery, its supra-clinoid part in 2 7 % . Vasospasm occurred in 3 8 % of multiple aneurysm cases. The aneurysms of different locations than those listed above, exhibit no spasm (fig. 2). Aneurysms of the same location can produce all types of vasospasm. VasoTable 5

Frequency of pre-operative vasospasm and distribution of vasospasm types after SAH in 106 cases of ruptures aneurysm of group B

time after

patients

patients with-

SAH

total

out vasospasm

typ I

< 3

patients with vasospasm typ II

typ III

total 16 ( 3 2 . 7 % )

49

33 ( 6 7 . 3 % )

10

5

1

4- 7

19

12 ( 6 3 . 2 % )

4

1

2

7 (36.8%)

8-14

17

6 (35.3%)

3

5

3

11 ( 6 4 . 7 % ) 5 (62.5%)

15-21

8

3 (37.5%)

1

3

1

22-28

5

4 (80.0%)

1

-

-

1 (20.0%)

> 28

8

6 (75.0%)

2

-

-

2 (25.0%)

106

64 ( 6 0 . 4 % )

21

total typ 1: spasm

"local"

vasospasm;

typ

II:

"multisegmental"

14 vasospasm;

7 typ

42 (39.6%) III:

"diffuse"

vaso-

372

O. Hey, K. Schürmann and S. Exner

T-fork m i d d l e c e r e b r a l a. anterior

com. a.

anterior

c e r e b r a l a.

mult,

aneurysm

c a r o t i d a. supraclinoid

part

others 10 Fig. 2

20

30

40

50

60

70

8 0 P a t j e n t s 100 [ % 1

Frequency of vasospasm in relation to localization of aneurysm in 106 cases of ruptured aneurysms in group B.

spasm in cases of aneurysm, in the region of the anterior communicating artery " l o c a l " VS is most frequent (62.5%). A similar behaviour can be found in vasospasm of the cerebri media: " L o c a l " VS in 4 5 . 5 % , "multisegmental" VS in 3 6 . 4 % and diffuse VS in 18.1%. Vasospasm following carotid aneurysm showed a " l o c a l " type and a multisegmental of equal frequency (42.9%) and a diffuse VS in 1 4 . 2 % .

Ventricular SAH

haemorrhage

Intracerebral haematoma • SAH Diffuse

]50

SAH

Vasospasm HI

Local

SAH

Minimal

10 Fig. 3

20

^

Multiseg.

•

Local n * 99

22

SAH

Diffuse

30

¿0

50

60

70

8 0 p a t j e n t s 100 1 % )

Frequency of vasospasm in relation to extravasal amount of blood in 99 cases of ruptured aneurysms in group B, estimated by computer tomography. Diffuse SAH: all basal cisterns filled with blood Local SAH: Blood only in surrounding of vessel Minimal SAH: Little evidence for blood

Vasospasm, its effect on timing the treatment for aneurysm of cerebral vessels

373

Comparison between amount of blood and vasospasm The frequency dependence of vasospasm from the amount of bleeding (CT evidence) from SAH is illustrated in figure 3. The cases having had blood filled ventricles and subarachnoidal spaces, have the highest rate of spasm (59%). In contrast to a diffuse subarachnoidal haemorrhage, filling all basal cisterns, a minimal bleeding into the cisterns causes "local" vasospasm only (22%).

Influence of vasospasm on pre-operative course At the time of admission patients suffering from VS can be graded I—V (tab. 6). Clinical symptoms were present in 20 patients graded III, IV or V. During the waiting period 5 patients deteriorated, 4 of these belonged to the lower risk grading I—II, 3

Table 6

Pre-operative course (HH grading) in 42 patients suffering from vasospasm at admission time until operation, group B grade at operation

grade at admission grade I:

6

grade II:

9

grade III:

4 —

grade II:

grade I

grade II

grade III: grade IV: grade V: grade I: grade II: grade III:

grade III

grade IV: grade V: grade II: grade III: grade IV: arrow down = deterioration (5 patients) arrow up = improvement (25 patients) arrow horizontal = unchanged (12 patients)

grade IV

374

O. Hey, K. Schurmann and S. Exner

patients of grade III, one patient grade IV and one patient of grade III after IV. While waiting for operation 25 patients improved, 13 changed from grade II/III to grade I, 8 to grade III after II and 4 patients from grade IV/V to II/III (s. tab. 6).

Timing of operation and mortality The interval between bleeding and operation illustrated in table 7 elucidates the degrees of risk in relation to the days between SAH and operation. Im grade I and II cases an operation was performed in 21 patients in the acute stage, in some instance within 3 days or 4—7 days after SAH. The operational mortality in this period was 14.3% and 7.1%. In the second and third week the mortality was 11.1% and 10.5%. Patients classified as grades IV and V had a mortality rate of 66.7% within 3 days after the bleed and 2 5 % if the operation took place after the second week p. SAH. When summarizing all results without considering the grading, the mortality rate for an early operation (within the first week) is 16% (4/24 pat.) higher than in patients operated later. The mortality rate for a late operation (after the first week) is 11.1% (9/81 pat.). The total mortality in group A (1956-1978) was significantly higher (22.5%) than in group B (1979-1982) of 11.7%. Vasospasm delays the onset of operation, for 5 % of patients with vasospasm could be operated on within the first week after SAH, in contrast to 6 6 % after the third week of SAH (fig. 4). The Table 7

Timing of operation and mortality in relation to riskgrading in 106 cases of ruptured aneurysm, group B Interval between last SAH and operation (days) 8-15 >15 total

1-3

4-7

grade at

no. of cases

no. of cases

no. of cases

no. of cases

no. of cases

operation

no. of deaths

no. of deaths

no. of deaths

no. of deaths

no. of deaths

mortality (%)

mortality (%)

mortality (%)

mortality (%)

mortality (%)

1,11

7

14

9

57

1

1

1

6

(14.3%) III

(10.5%)

1

1

10

-

0

1

0

(0.0%)

(100%)

(0.0%)

3

—

-

4

2

-

-

1

-

-

10

15

3

1

(66.7%) total

(11.1%)

—

-

IV, V

(7.1%)

(30.0%)

(6.7%)

87 9 (10.3%) 12 1 (8.3%) 77 3

(25.0%)

(42.8%)

10

71

106

2

7

(20.0%)

Early operation: operation within 7 days after last SAH Late operation: operation later than 1 week after last SAH

(9.8%)

13 (12.2%)

Vasospasm, its effect on timing the treatment for aneurysm of cerebral vessels

80-1 [%)

I

70-

m

I no Spasm

66

I Spasm

60-

375

n = 106

50AO-

o

45 36

302010

10ri u Fig. 4

By

I

1.

Hsj >3

2.

time in w e e k s

Interval between last SAH and operation in 4 2 cases of aneurysm with vasospasm and 64 patients without vasospasm (group B).

pre-operative vasospasm shows no effect on the death rate (tab. 8). The mortality in the group "without spasm" was significantly higher (17.2%) than in the vasospasm group (4.8%). This observation is still valid even if the post-operative vasospasm cases (20 pat.) are included. Only one patient from this group succumbed the consequences of post-operative vasospasm. Within the first week after aneurysm operation 7 patients deceased, in the second week to the fourth week 5 patients and one patient after 138 days.

The final post-operative outcome The examinations of the survivors revealed that a total of 7 4 . 8 % of the patients fullfilled the criteria for being classified "capable of work" (tab. 9). Grad I and II patients present with 8 2 . 4 % a significantly better prognosis than those graded III, IV and V. Distinct neurological signs still present in a review of the cases were present in Table 8

The effect of vasospasm on death rate in 106 cases of ruptured aneurysm, group B no spasm

vasospasm

total

deceased

11 ( 1 7 . 2 % )

2 ( 4.8%)

13 ( 1 2 . 3 % )

survival

53 ( 8 2 . 8 % )

40 ( 9 5 . 2 % )

93 ( 8 7 . 7 % )

total

64 ( 1 0 0 % )

42 ( 1 0 0 % )

106 (100%)

376 Table 9

O. Hey, K. Schurmann and S. Exner Post-operative quality of life in survivors (outcome) and mortality in 111 cases of aneurysm, group B

grade at operation

no. of patients

no. of 'able to work'

no. of 'not able to work'

no. of deaths

I, II III IV, V

91 13 7

75 (82.4%)* 8 (61.5%)* 0 ( 0.0%)

7 ( 7.7%) 4 (30.8%) 4 (57.2%)

9 ( 9.8%) 1 ( 7.6%) 3 (42.8%)

total

111

83 (74.8%)*

15 (13.5%)

13 (11.7%)

* able to work'/survivors

30.8% of grade III patients. 57.2% of grade IV and V patients were classified to be vegetable-like survivors. In contrast to its influence on mortality vasospasm influences the post-operative results of survivors in a negative way. No neurological deficits were found in 39.7% only of the patients of the "spasm group" in contrast to 60.3% in the non-spasm group (tab. 10). Remaining neurological defects of vasospastic patients were present in 60% and much higher than in the group used for comparison (40%).

Discussion The consequences of cerebral vasospasm and the re-bleeding are both the greatest problems confronting the clinicians in treating aneurysm [14, 22], It is known that after aneurysm rupture, vasospasm usually begins on the fourth day and reaches a maximal extent between the eighth and fourteenth day [7,17,21,29]. To operate on in these phase can worsen the existing vasospasm and causes considerable ischaemic damage to the brain. The evidence of pre-operative vasospasm of 39.6% in our clinical cases agrees well with the experience of other angiographic studies [7, 8, 11]. The moment of occurrence of cerebral vaso-constriction and the type of vasospasm play a decisive role for the clinical judgement. The highest rate of vasospasm is found in the second and third week after SAH reaching 64.7% and 62%. Within 3 days after SAH a spasm could be proved angiographically in 32.7%, in the fourth week in 20% and after the Table 10

Outcome of survivors in vaso-spastic group and non-spastics

findings

no. of survivors

no. of survivors without vasospasm with vasospasm

'able to work' 'not able to work'

78 15

47 (60.3%) 6 (40.0%)

31 (39.7%) 9 (60.0%)

Vasospasm, its effect on timing the treatment for aneurysm of cerebral vessels

377

fourth week in 2 5 % . The same frequency was found by other authors as well, e.g. Weir et al. [27] found a frequency of 31 % between the sixth and twelfth day, Hamer [7] a rate of 6 0 % within the 4 - 1 2 day after a bleeding, Sano [21] found vasospasm in 6 6 % of 443 cases between the sixth and nineth day after SAH. According to Sano's definition, the vasospasm pattern was classified angiographically into local, multisegmental and diffuse. In this way one succeeds recognizing the degree of narrowing of cerebral vessels and reaches the conclusion that not every vasospasm causes clinical symptoms, which may appear, if other factors, e.g. cardio-pulmonary contribute, or failure of cerebral vascular auto-regulation and of regional bloodflow [25]. In our examination of 42 patients suffering from vasospasm 21 patients (50%) had "local", 14 (33.3%) multisegmental and 7 (16.7%) a diffuse vasospasm. Similar distributions were found by others [7, 21]. Aneurysm of the same location can cause all three types of spasm, but aneurysm in the region of the anterior communicating and cerebri media are mainly related to the "local" type of spasm. Aneurysms of the carotid interna show an equal distribution of local and multisegmental spasm. In 12 patients the neurological signs did not change until operation, 5 worsened and in 25 improved. A dependence of blood distribution (seen in CT) and the appearance of vasospasm could be proved only for the group of intraventricular bleedings and SAH, resulting in spasm in 5 9 % of cases. For the other groups with differently distribution sites of bleeding (fig. 3) the majority of patients did not suffer from angiospasm. No obvious correlation between vasoconstrictory properties from disintegrating red blood cells in CSF [13] and clinically manifest vasospasm could be established. Only five percent of our cases from the spasm group with a low risk grade of I and II without vasospasm were operated on within the first week after SAH. The preoperative vasospasm delayed in all other patients the operation considerably and necessitated in 6 6 % of vasospasm cases a postponment of operation until after the third week (fig. 4). The timing for operation was fixed after a waiting period, when regional bloodflow measurements or a control angiography gave no evidence for vasospasm. The presence of pre-operative cerebral vasospasm was without influence on the mortality rate related to operations, which was defined as the total number of death occurring within the observations time of six months. The mortality of the spasm group was lower (4.8%, 2/42 patients) than in the comparable non-spasm group (17.2%, 11/64 patients). However the negative and detrimental effect of vasospasm was clearly shown in the outcome of survivors after six months and in control examinations later on. Only 3 9 . 7 % of spasm cases fullfilled the criteria for being defined, "capable of work" in contrast to 6 0 . 3 % of patients without vasospasm. In one large single study [11] dealing with operated aneurysms of the anterior communicating artery (346 cases) the mortality rate was found to be 5 . 5 % but a rate

378

O. Hey, K. Schiirmann and S. Exner

of 24% in those cases operated on between the third and seventh day, and only half of those early operated showed a favourable outcome. The most frequent cause for this high mortality was the p.o. vasospasm. For this reason, the Japanese neurosurgeons recommend performing the operation in the acute stage (1—3 days after SAH) in grade I and II patients only (11, 17, 21, 24) and wash out the cisternal bleedings most thoroughly. This procedure is said to reduce the vasoconstrictory activity of disintegrating blood and positively affects p.o. mortality and debility [8, 17, 24, 29]. The published results of early and late operations differ considerably, as they were based on different therapeutic concepts. However a common factor is the lower mortality and morbidity for the grades I and II patients. Hotta [11a] reports a mortality rate of 52% (16/31 patients) when operating within six hours after SAH, of 32% (12/27 patients) within 12 hrs, of 12% (8/53 patients) within 24 hrs and 23% (10/43 patients) within 72 hrs. However Sano [21] saw a mortality rate of 0% within 72 hrs (0/22 patients), of 15.2% (5/33 patients) within the first week, of 18% (5/28 patients) within the 3rd-14th day accounting for a total mortality of 5% in 403 cases. Suzuki [24] reports a mortality rate of 2.3% (1/43 patients) when operating within 48 hrs after SAH, of 4% (3/75 patients) within the 3rd-14th day and 2.8% (4/145 patients) when waiting more than 15 days after SAH. The total mortality amounted to 3% (8/263 patients). Guidetti [6] has a mortality rate of 21% (19/92 patients) operating early within the first week and of 1.5% (1/64 patients) when operating late, total mortality was 11.5% (23/200 patients). A recent comparative study from a number of Japanese clinics reports on 4238 cases of aneurysm [9] graded I—V and compares mortality and outcome of early and late operations most impressively. Two groups of patients were considered, one operated on early, the other late. For both groups (2670 patients and 640 ops) when considering all grades, the mortality rate of late operated cases was significantly lower than in early operations, late op = 12.2% resp. 10%, early op = 40.7% resp. 50.4%.

Summary From 111 patients suffering from aneurysm of cerebral vessels, 106 patients with ruptured aneurysm were examined, whose operational timing and prognostic chances were well documented (group B, 1979-1982). Furthermore relevant data of a previous series of 200 cases of cerebral aneurysm, treated between 1956—1978 were used (group A). Vasospasm and its factors influencing operation-timing and outcome were analysed and the final results of early and late operation have been compared. The patients were graded according to Hunt and Hess assessing the risks involved. The percentages of recurrent bleeding were in group A 36.5% and 28% in

Vasospasm, its effect on timing the treatment for aneurysm of cerebral vessels

379

group B. The incidence of vasospasm (as seen in angiography) was in group B 39.6% (42/106 patients). The highest rate of vasospasm in the spasm group division B was found to occur in the second and third week after SAH and amounted to 64.7% and 62.5%. In 42 cases of vasospasm 21 patients exhibited a "local", in 14 patients, a "multisegmental" and in seven a "diffuse" vasospasm. Among the cases with blood filled ventricle and subarachnoidal spaces were 59% vasospastic. Vasospasm postponed the moment for operating considerably and only 5% of this vaso-spastic group could be operated on within the first week after SAH. A pre-operatively present VS had no negative effects on the mortality rate, but influenced the outcome for the survivors detrimentally. The mortality rate for early operation (within the first week after SAH) was 16% (4/25 patients) and for the late operation 11.1% (9/81 patients). The total mortality in group A (1956-1978) was 22.5% and in group B (1979-1982) 11.7%. If this mortality rate and the outcome in early and late operations are analysed, it can be shown that cases, late operated on, fare not worse.

References [1] Bohm, E. and R. Hugssor: Result of surgical treatment of 200 consecutive cerebral aneurysm. Acta Neurol. Scnad. 46, 43-52 (1979). [2] Clarisse, J., M. Jomin, L. Andressi and E. Laine: Prognostic significance of cerebral spasm in the course of meningeal haemorrhage. Neuroradiology 3, 150—152 (1972). [3] Drake, C. G.: On the surgical treatment of ruptured intracranial aneurysms. Clin. Neurosurg. 24, 122-155 (1977). [4] Fisher, C. H., J. P. Kistler and J. M. Davis: Relation of cerebral vasospasm to subarachnoid haemorrhage visualized by computerized tomographic scanning. Neurosurgery 6, 1—9 (1980). [5] Giannota, S. L. and G. W. Kindt: Total morbidity and mortality rate of patients with surgically treated in intracranial aneurysms. Neurosurgery 4, 125—128 (1979). [6] Guidetti, B.: Microsurgical treatment of intracranial sacular aneurysm. Acta Neurochir. 43, 153-162 (1978). [7] Hamer, J.: The significance of cerebral vasospasm with regard to early and delayed aneurysmal results of early surgery. Acta Neurochir. 63, 209-213 (1982). [8] Hashi, K., K. Nin and K. Shimotake: Surgery in the prevasospastic interval. Acta. Neurochir. 63, 141-145 (1982). [9] Hata, S., S. O. Dal and S. Ishii: Cooperative study on ruptured aneurysm in Japanese neurosurgical clinics. Neurol. Med. Chir. (Tokyo) 23, 30-40 (1983). [10] Hey, O. and K. Schiirmann: Timing of aneurysms of cerebral vessels. Documentation of 200 patients in a retrospective study. In: W. Schiefer, M. Klinger and M. Brock (Eds.): Advances in Neurosurgery, Vol. 9, pp. 233-237. Springer, Berlin-Heidelberg-New York 1981. [11] Hori, S. and J. Suzuki: Early intracranial operation for ruptured aneurysms. Acta Neurochir. 46, 93-104 (1979). [11 a] Hotta, T., S. Tokuda, M. Nishiya, Y. Tanaka and J. Nakamura: Surgical results of intracranial ruptured aneurysms in the acute stage. Acta Neurochir. 63, 193-200 (1982). [12] Hunt, W. E. and R. M. Hess: Surgical risk as related to time of intervention in repair of intracranial aneurysms. J. Neurosurg. 28, 14-20 (1968).

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O. Hey, K. Schürmann and S. Exner

[13] Hunt, T. M., G. DuBoulay, W. P. Blaso, D. M. Forster and D. J. Boullin: Relationship between presence of vasoconstrictor activity in cerebrospinal fluid and time after subarachnoid haemorrhage from rupture of cerebral arterial aneurysms. J. Neurol. Neurosurg. 42, 625-634 (1979). [14] Kim, H., M. Mizukami, T. Kawase et al.: Time course of vasospasm its clinical significance. Neurol. _ Med. Chir. 19, 95-102 (1979). [15] Krayenbühl, H. A., M. G. Yasargil, E. S. Flamm and J. M. Tew: Microsurgical treatment of intracranial saccular aneurysms. J. Neurosurg. 37, 678—686 (1982). [16] Marshall, W. H.: Delayed arterial spasm following subarachnoid haemorrhage. Radiology 106, 325-327 (1973). [17] Ohta, H., Z. Ito, N. Yasui and A. Suzuki: Extensive evacuation of subarachnoid clot for prevention of vasospasm — Effective or not? Acta Neurochir 63, 111-116 (1982). [18] Pool, J. L.: Bifrontal craniotomy for anterior communicating artery aneurysms. J. Neurosurg. 36, 212-220 (1972). [19] Saito, J. and K. Sano: Vasospasm following rupture of cerebral aneurysms. Neurol. Med. Chir, (Tokyo) 19, 103-107 (1979). [20] Samson, D. S., R. M. Hodosh, W. R. Reid, C. W. Beyer and W. K. Clark: Risk of intracranial aneurysm surgery in the good grade patient: Early vesus late operation. Neurosurgery 5, 422—426 (1979). [21] Sano, K. and I. Saito: Timing and indication of surgery for ruptured intracranial aneurysms with regard to cerebral vasospasm. Acta Neurochir. 41, 49-60 (1978). [22] Sundt, T. M., S. Kobayashi, N. C. Fode and J. P. Whisnant: Results and complications of surgical management of 809 intracranial aneurysms in 722 cases. J. Neurosurg. 56, 753-765 (1982). [23] Suzuki, J., T. Onuma and T. Yoshimoto: Results of early operations on cerebral aneurysm. Surg. Neurol. 11, 407-412 (1979). [24] Suzuki, J., N. Kodama, T. Yoshimoto and K. Mizoi: Ultraearly surgery of intracranial aneurysms. Acta Neurochir. 63, 185-191 (1982). [25] Symon, L.: Discordered cerebro-vascular physiology in aneurysmal subarachnoid haemorrhage. Acta Neurochir. 41, 7 - 2 2 (1978). [26] Taneda, M.: The significance of early operation in the management of ruptured intracranial aneurysm - An analysis of 251 cases hospitalized within 24 hours after subarachnoid haemorrhage. Acta Neurochir. 63, 201-208 (1982). [27] Weir, B., M. Grace, J. Hansen and C. Rothberg: Time course of vasospasm in man. J. Neurosurg. 48, 173-178 (1978). [28] Wilkins, H. R.: The role of intracranial arterial spasm in the timing of operation for aneurysm. Clin. Neurosurg. 24, 185-207 (1977). [29] Yasui, N., Z. Ito, H. Ohta and A. Suzuki: Surgical problems and pathophysiology in severe cases with ruptured aneurysm in the acute stage. Acta Neurochir. 63, 163-174 (1982). [30] Yoshimoto, T., K. Uchida, U. Kaneko, T. Kayama and J. Suzuki: An analysis of follow-up results of 1000 intracranial saccular aneurysms with definite surgical treatment. J. Neurosurg. 50, 152—157 (1979).

Treatment of arterial spasm after aneurysmal surgery and subarachnoid haemorrhage with induced hypertension H. J. Klein, H.-P. Richter, M. Schäfer, S. Bien

Introduction Intracranial arterial spasm is a well-known complication after subarachnoid haemorrhage and after surgery for intracranial aneurysms [2, 3, 5, 6, 11]. Different methods have been proposed to cope with this problem and to overcome its clinical sequelae such as impaired consciousness, hemiparesis or aphasia [3]. One treatment consists in the induced hypertension with dopamine [2, 3, 5, 6, 11]. Our experience with continuous treatment in 21 patients suffering of cerebral vasospasm after aneurysm surgery is reported.

Material and methods Among 140 patients operated for intracranial aneurysms from January 1978 to April 1983, 39 (28%) showed clinical signs of vasospasm postoperatively. In 17 patients vasospasm was proved by angiography. All patients were examined by postoperative CT-scans, 38 patients had no computertomographical evidence for intracerebral haematomas. Onset of symptoms occurred in 23 patients as a gradual disturbance of consciousness followed by hemiparesis and aphasia (11 resp. 5 patients). Sex distribution showed 2 2 male and 17 female patients, the mean age was 47,4 years. Those patients who underwent a treatment with dopamine represent a mean age of 43,9 years, whereas in the group without induced hypertension the mean age was 54,2 years. The location of the aneurysms is shown in table 1. 21 of the 39 patients were treated by induced hypertension with dopamine. Those patients with haemorrhagic infarction (2), cardiac arrhythmias (2) and intracrebral haematoma (1) did not receive this treatment. Two patients developed arrhythmia after some minutes and one patient after two hours of dopamine treatment. We did not medicate dopamine by following a fixed dosage schedule. The dosage was adjusted individually in response to the clinical signs. Dopamine was given by

382 Table 1

H. J. Klein, H.-P. Richter, M. Schäfer and S. Bien Results and location of aneurysm

Patients with dopamine treatment

Patients without dopamine treatment

Complete recovery: 7 2 A. carotis interna 1 A. communicans posterior 3 A. cerebri media 1 A. communicans anterior

Complete recovery: 1 1 A. communicans posterior

Mild paresis: 6 2 Bifurcatio 2 A. cerebri media 1 A. communicans anterior 1 A. cerebri anterior

Mild paresis: 0

Moderate aphasia and paresis: 3 1 Bifurcatio 1 A. cerebri media 1 A. communicans anterior

Moderate aphasia and paresis: 3 2 A. cerebri media 1 A. carotis interna

Severe aphasia: 1 1 A. cerebri media Severe paresis: 1 1 A. communicans anterior

Severe aphasia: 0

Severe paresis and aphasia: 0

Severe paresis and aphasia: 2 2 Bifurcatio

Exitus letalis: 3 1 A. carotis interna 2 A. communicans anterior

Exitus letalis: 9 2 A. carotis interna 6 A. communicans anterior 1 Bifurcatio

Severe paresis: 3 2 A. cerebri media 1 A. cerebri anterior

continuous intravenous drip infusion at a rate of 5 - 6 2 microgram/kg/min. to maintain systolic blood pressure at levels of 150—190 mm Hg. In all patients the dosage had to be increased after 12—36 hours as dopamine causes a permanent release and gradual loss of noradrenaline from the myocardium [4]. After a successful treatment, by means of reduction of focal neurological signs, dopamine was gradually decreased to prevent an unfavourable and unwanted drop in systemic blood pressure. In 13 patients dopamine caused a moderate tachycardia (up to a heart rate of 112/min.) necessitating additional treatment with digitalis in 6 patients. The maximum period of dopamine application was 5 weeks. Patients in whom intracranial pressure was increased at the same time, as shown by lumbar puncture or continuous intracranial epidural monitoring, received a bolus infusion of 30 g mannitol initially, followed by additional 150—187,5 g in 24 hours. The most important parameter concerning the effect of dopamine on the cerebral vasospasm was its influence on the

Treatment of arterial spasm after aneurysmal surgery and subarachnoid haemorrhage

383

neurological signs. In addition, we measured the global hemispheric blood flow after bolus injection via a centrally placed venous catheter of 10—12 mCi of " T e c h n e tium pertechnetate using a gamma-camera (Ohio Nuclear O N 100) in 5 patients with vasospasm and dopamine infusion. The basic EEG rhythm was recorded using a frequency analyser in two patients. All patients with dopamine treatment showed a considerable increase of urinary excretion and daily fluid balances up to 7 liters.

Results Seven of the 21 patients with induced hypertension underwent a complete recovery. Six retained a very mild paresis (Results and location tab. 1). In three patients a moderate aphasia and paresis persisted. One patient retained a severe aphasia and another patient showed a severe paresis of the left arm und leg without significant improvement and three patients died. However the clinical outcome of the 18 patients not receiving dopamine or any other treatment for alleviating intracranial vasospasm proved to be worse: Only one had a complete recovery. Three patients showed a persisting moderate paresis and aphasia and five other patients a hemiplegia without signs of improvement, two of them had a severe aphasia; of these 18 patients 9 died of increased intracranial pressure. In 8 of the 18 patients an induced hypertension with dopamine was contra-indicated for the following reasons: They either had an intracerebral haematoma (1), a hemispheral infarction (2), cardiac arrhythmia (5), 3 cases developed cardiac failure due to induced hypertension. The clinical course of the patients was the main criterion for judging the effect of dopamine on cerebral vasospasm. In addition we estimated the cerebral blood flow after bolus injection of 10—12 mCi of " T e c h n e t i u m pertechnetate in 5 patients subjected to dopamine infusions before and after the beginning of the induced hypertension. All of them showed a decreased global blood flow on the side of the vasospasm as compared to the unaffected hemisphere and noted under treatment with dopamine a distinct increase in blood flow on the side of the vasospasm. Frequency analysis of the basic EEG rhythm (Intertechnique) showed no change in the pattern of healthy volunteers who had received different dosages of dopamine. However patients with vasospasm showed a significant reduction of slow waves or an increase of alpha rhythm after dopamine infusion (fig. 1).

Discussion and summary Although cerebral blood flow studies were not carried out in five patients, only the clinical results suggest that the dopamine-induced-hypertension may improve cerebral perfusion and neurological deficits caused by vasospasm. Auto-regulation is

384

Fig. l a

H. J. Klein, H.-P. Richter, M. Schäfer and S. Bien

In healthy volunteers, dopamine, even in very high dosages, does not change the EEG as revealed by frequency analysis at a 3 minutes' period.

poor or absent in patients with severe vasospasm and cerebral blood flow follows the mean arterial pressure [2, 8, 10, 12]. Clinical and experimental data of other authors [2, 10] support the thesis that the initial patho-physiological event leading to a clinical deterioriation is caused by the reduction of CBF due to spastic narrowing of the arteries. In cases of severe and prolonged spasm the critically diminished perfusion rate causes a cerebral ischaemia which may be followed by vasogenic oedema and consecutive increase of intracranial pressure. We, therefore, treated these patients as early as possible at the onset of symptoms as no other valuable and practicable parameter for detecting the beginning of angiospasm exist. Arteries constricted by spasm do not normally react to auto-regulating factors such as hypertension by further reducing the vessel's diameter until maximal muscular constriction results [2, 10]. A therapeutical induced blood pressure elevation results in an increased CBF by an elevated stroke volume (cardiac output) and an elevated peripheral resistance. This increased CBF is achieved by giving dopamine infusions exerting a positive inotrope effect. A contin-

Treatment of arterial spasm after aneurysmal surgery and subarachnoid haemorrhage

385

SKALIERUNG 2.01 HZ/DXV

Fig. l b

In patients with vasospasm the EEG shows a slower alpha rhythm before dopamine infusion (O). A moderate dosage of dopamine (8—10 microgram/kg/min.) increases the alpha rhythm.

uous arterial spasm causes a progressive deterioriation with additional complications and the induced hypertension by dopamine, is only reasonable at the onset of symptoms and not later on, when vasogenic oedema and blood-brain-barrier disturbances are apparent [6,]. The improvement of neurological deficits was associated with an improvement of EEG in those two cases shown by telemetric computed EEG frequency analysis. It must be emphasized however that sustained increases in blood pressure may result in severe increases in ICP. Therefore careful monitoring and control of the ICP is important in patients with dopamine-induced-hypertension. In 8 cases with increased ICP the patients was given an intravenous bolus injection of mannitol initially, followed by further infusions of 1 0 0 0 - 1 2 5 0 ml 1 5 % mannitol per 24 hours continously depending on the actual ICP which was controlled by lumbar punctures or intracranial (epidural) pressure monitoring based on the Gaeltec system. It was evident that mannitol infusions reduce the pressure volume relationship earlier and more pronounced than the ICP itself, and by this influencing the volume pressure quotient positively. Thus this action counteract the tendency of the dopamineinduced-hypertension to worsen intracranial pressure and might possibly lead to elevated ICP [ 2 , 7 , 9 ] . Moreover it reliably reduces ICP and may improve the cerebral blood flow. It seems reasonable, that the combination of a dopamine-induced hypertension and a continuous infusion of mannitol would be beneficial. This therapy

386

H . J. Klein, H.-P. Richter, M . Schäfer and S. Bien INCREASE OF DOPWIfE DOSAGE DURING TOE PERIOD WITH INDUCED HYPERTENSION MICROGRAM KG/ MIN,

5 H

]7 14

12 10

2

2

1

21'

I

M=21

0

1

2

3

H

5

6

M M W w w y Fig. 2

7

8

91C1I1213M1516171819MYS

w m s z s a s z u w i w s i M L S M M

LITER

Range of dopamine dosage in 2 1 patients with induced hypertension. Daily fluid balance (average of infusions and urinary excretion) in the same patients.

forces the clinician to give large amounts of fluid reaching 5 - 9 liters per day to maintain a high blood volume and to prevent its depletion by mannitol due to the renal action of dopamine and to support the hypertensive properties of dopamine [4], The rapid turnover of large amounts of intravenous infusions and urinary excretion makes it necessary to control the serum electrolytes in short intervalls (fig. 2). Estimation of global cerebral blood flow using a gamma camera after bolus injection of " T e c h n e t i u m pertechnetate is relatively simple allowing the observation of distinct differences in blood flow between the spastic and the non spastic cerebral hemisphere. An increase in blood flow after dopamine infusions in the ischaemic area would be detected as well. Due to the intact auto-regulating properties in the non spastic vessels a small reduction of blood flow occurs in the contralateral hemisphere in dopamine-induced-hypertension. We believe, that early dopamineinduced-hypertension combined with a very careful supervision of the clinical course should prevent a progressive deterioriation of the patients suffering from arterial spasm after aneurysmal surgery.

Treatment of arterial spasm after aneurysmal surgery and subarachnoid haemorrhage

387

References [1] Boisvert, D. P., T. R. Overton, B. Weir and M. Grace: Cerebral arterial responses to induced hypertension following subarachnoid haemorrhage in the monkey. J. Neurosurg. 49, 75-83 (1978). [2] Brown, F. D., K. Hanlon and S. M. Mullan: Treatment of aneurysmal hemiplegia with dopamine and mannitol. J. Neurosurg. 49, 525-529 (1978). [3] Flamm, E. S.: Antifibrinolysis and the preoperative mangement of subarachnoid haemorrhage. In: Clinical management of intracranial aneurysms. Seminars in neurological surgery Raven Press, New York 1982. [4] Goldberg, L. J.: Dopamine-Clinical Uses of an Endogenous Catecholamine. The New England Journal of Medicine, 291, 707-710 (1974). [5] Klein, H. J.: Induced hypertension in the treatment of arterial spasm following aneurysm surgery and subarachnoid haemorrhage. Acta Neurochirurgica 62, 112 (1982). [6] Kosnik, E. J. and W. E. Hunt: Postoperative hypertension in the management of patients with intracranial arterial aneurysms. J. Neurosurg. 45, 148-154 (1976). [7] Leech, P. and J. D. Miller: The effect of mannitol, steroids and hypocapnia on the intracranial volume/pressure response. In: ICP II, pp. 361—364. Springer-Verlag, Berlin 1975. [8] Merory, J., D. J. Thomas, P. R. D. Humphrey, G. H. Du Boulay, J. Marshall, R. W. Ross Russell, L. Symon and E. Zilkha: Cerebral blood flow after surgery for recent subarachnoid haemorrhage. Journal of Neurol. Neurosurg. Psychiat. 43, 214-221 (1980). [9] Miller, J. D. and P. Leech: Effects of mannitol and steroid therapy on intracranial volume-pressure relationships in patients. J. Neurosurg. 42, 274—281 (1975). [10] Symon, L.: Disordered cerebrovascular physiology in aneurysmal subarachnoid haemorrhage. Acta Neurochir. 41, 7 - 2 2 (1978). [11] Tsujita, Y., H. Nawata and H. Sugiyama: Dopamine-induced hypertension treatment for cerebral vasospasm after subarachnoid haemorrhage. Abstracts of the 7th International Congress of Neurological Surgery. Supplement to Neurochirurgia. Thieme-Verlag, Stuttgart, New York 1981. [12] Waltz, A. G.: Effect of blood pressure on blood flow in ischaemic and in nonischaemic cerebral cortex. The phenomena of autoregulation and luxury perfusion. Neurology 18, 613-621 (1968).

The use of nimodipine in patients following subarachnoid haemorrhage B. Weir

Allen [1] suggested that since cerebral vascular smooth muscle cells require Ca e 2 + to contract in response to a wide variety of agonists, in contrast to non-cerebral arteries, agents such as verapamil might block contraction of cerebral arteries without interfering with noncerebral arterial tone. He organized a multi-institutional, prospective, double-blind, randomized, placebocontrolled trial of nimodipine [2]. One hundred and twenty-five neurologically normal patients, who were within 96 hours of their subarachnoid haemorrhage were studied, to test whether treatment with this calcium entry blocker would prevent or reduce the severity of ischaemic neurologic deficits from arterial spasm. Entry was limited to patients who were essentially normal in order to accurately assess the development of neurological deficits from spasm. Between the end of 1979 and mid 1982, 125 cases were treated. The initial oral dose of nimodipine was 0.7 mg/kg body weight (adjusted to the nearest 10 mg capsule) followed by 0.35 mg/kg every four hours for 21 days. Within 48 hours of the development of a neurological deficit, if any developed after admission, a CT scan and angiography were carried out. Surgery was performed any time up to 14 days of study entry. In analysing for efficacy, the end points were: 1. the development of a neurological deficit from spasm and, 2. the severity of such deficit at 21 days from the start of the treatment. The exclusion of nine patients for failing to meet entry criteria or having protocol violations, did not prejudice the analysis in favour of nimodipine. Eight of 60 patients given placebo either died or still had severe deficits from spasm at the end of the 21 day treatment period. Only one of the 56 treated cases had died from spasm and there were no cases with severe deficit. This difference was significant (p = 0.03, Fisher's exact test). Numerous characteristics of the placebo and nimodipine groups were analysed but there were no apparent differences in respect to any factor other than the use of the drug. In particular, the groups had similar amounts of blood in initial CT scan, incidence of loss of consciousness, hypotension and concurrent illness. Patients on placebo who had severe outcomes showed more blood in initial CT scan than did

390

B. Weir

Table 1

Results of treatment with nimodipine Protocol compliant cases

Cause* of severe outcome at 21 days

Nimodipine

Placebo

(56 cases)

(60 cases)

Vasospam alone Severe deficit Death

0 ( 0%) 1 ( 2%)

5 ( 8%)

5 ( 9%) 0 ( 0%)

2 ( 3%)

3 ( 5%)

Vasospasm and other cause Severe deficit Death

2 ( 3%)

Cause other than vasospasm Severe deficit

5 ( 8%)

4 ( 7%) 2 ( 4%)

2 ( 3%)

Severe deficit

9 (16%)

12 ( 2 0 % )

Death

3 ( 5%)

7 (12%)

Death All causes

* Established by a committee unaware of the details of the treatment group.

placebo cases with good outcome. This was to be expected on the basis of previous experience. On the other hand, this was not true for the nimodipine group. Patients showing considerable spasm in angiogram made soon after the onset of the neurological deficit showed the most severe outcome at final assessment. Overall mortality was 1 2 % for the placebo group by the end of the 21 day treatment period and 5 % for the nimodipine group. This study had the limitation of relatively small numbers of patients with deficits due to spasm but the difference in results still achieve statistical significance. In addition, since all patients were not routinely angiogrammed, there was no direct evidence that nimodipine reduced the severity of incidence of vasospasm. A summary of this investigation is shown in table 1 [3]. Because no side effects were apparent, further studies are underway using different dosage levels, including some higher than in this initial human study.

References [1] Allen, G. S.: Cerebral arterial spasm: A discussion of present and fucture research. Neurosurgery 1, 1 4 2 - 1 4 8 (1977). [2] Allen, G. S., H. S. Ahn, T. J. Preziosi et al.: Cerebral arterial spasm — a controlled trial of nimodipine in patients with subarachnoid haemorrhage. New Engl. J. Med. 308, 6 1 9 - 6 2 4 (1983). [3] Battye, R.: Personal communication.

Preliminary observations on the use of nimodipine and Prostaglandine Ei in acute subarachnoid haemorrhage and ischaemic stroke H. P. Ammerer, R. Karnik, G. Perneczky

Treatment with nimodipine only started in January 1983; for this reason it is not yet possible to give a statistically significant evidence of our findings. So far 31 patients, selected according to the pattern of the multicentric study, have been trated with this calcium antagonist. Only those patients were selected in whom subarachnoid haemorrhage had occurred less than four days earlier and who were graded 1 to 3 on the Hunt and Hess scale. Our observations are still limited to intravenous application of nimodipine in dosages between 2 and 5 mg/h. In all patients treated with nimodipine an easy adjustment of the blood pressure was possible allowing to lower the systolic pressure below 140 mm Hg given in the acute phase. Heart rate and blood pressure problems have not occurred up to now. The patients were controlled in the intensive care unit and a preoperative systolic blood pressure between 90 and 100 mm Hg was considered acceptable, in younger patients even desirable. Prostin® (prostaglandine Ei) has only been administered together with nimodipine in three patients. We selected patients showing therapy-resistant spasm in spite of largedose administration of nimodipine (up to 5 mg/h). After starting the therapy with Prostin (5 ng/kg/min) the dosages of other drugs remained unchanged. Our experience in treating ischaemic stroke is greater and results from 16 cases can be reported. The treatment of these patients started within 48 hours after onset of the acute symptoms. Their average age was 60 years, the youngest patient was 26, the oldest 83 years old (tab. 1). Eight of the patients were females and eight males. Nine showed improvement and three full recovery. However, it should be kept in mind with these results, that ischaemic attacks are treated at the same time, and spontaneous remission could be of importance, too. Therefore we prefer to discuss neurologically unequivocal individual cases. We would like to stress a case of progressive stroke treated 32 hours after onset of the neurological symptoms. Within 2 days complete recovery of the patient was achieved; 2 weeks later a severe stenosis of the internal carotid artery was operated-

392 Table 1

H . P. Ammerer, R. Karnik and G. Perneczky Treatment of ischaemic strokes with Prostaglandine Ei number

unchanged

improved

normal

male

8

3

4

1

female

8

4

2

2

on. In view of the almost moribund state of the patient on admission, immediate operation had not been considered. In a second patient with carotid artery occlusion, who had been admitted with a hemiplegia which had occurred suddenly and had remained unchanged for 2 days, a complete elimination of the symptoms could be achieved within three days. The third remarkable case, a 32-year-old woman, showed an occlusion in the rostral part of the basilar artery. On admission the patient was somnolent, showed severe impairment of ocular muscle nuclei and changing dextro-cerebral symptoms, vertigo and vomiting. At the time of the latest control, the patient was without any neurological symptoms. In this case an extraintracranial anastomosis between the superficial temporal artery and superior cerebellar artery is planned.

Dosage of Prostaglandin Ei (tab. 2) In this connection the findings of Rhodes fl], who compared various dosages, should be pointed out. Olsson and Nilsson [3] achieved the best results in peripheral circulatory disturbances with a relatively low dosage of 5 ng/kg/min. We followed this suggestion and the recommendations of the Austrian Society against Arteriosclerosis [5]. The first 10 patients were treated 12 hours daily for five days, every pause of 12 hours being followed by 12 hours treatment, and so on. We started with 1 ng/kg/min. The dosage was increased to 5 ng/kg/min. within one hour. In the last 6 patients we carried out this course of treatment continuously for 72 hours. The slow increase during the first hour was maintained. Complications in the form of an easily controlled increase in blood pressure occurred only in two patients. In the above mentioned 31 patients only 4 failed to respond to nimodipine. The first patient died of extensive malacia following the appearance of diffuse spasm on the second postoperative day (tab. 3).

Table 2

D o s a g e of prostaglandine Ei

1 ng/kg/min within one hour increasing to 5 ng/kg/min 12 hours daily for 5 days

Preliminary observations on the use of nimodipine and prostaglandin Ei Table 3

393

Therapeutic failure: 4 cases

case

operation date after bleeding

occurrence of spasm

treatment with prostin

1 2 3 4

Id 5d Id Id

3d 9d 4d 3d

none failure failure successful

The operation of a large aneurysm of the anterior communicating artery (fig. 1) was performed without complications 48 hours after the first subarachnoid haemorrhage. Both the pre-operative and the usual immediate post-operative angiogram still did not show any spasm. Treatment with imodipine was started on the day bleeding occurred. The maximum dosage was still 3 mg/h. In the second case, a fifty-year-old woman (fig. 2), spasm occurred on the fifth postoperative day following an equally uneventful operation. The patient, who at first had no neurological deficit, is now suffering from an apallic syndrome and is

Fig. 1

Arrest of cerebral bloodflow following severe arterial spasm in a patient after early operation of an aneurysm of the anterior communicating artery.

a)

Fig. 2

b) Aneurysm of the right middle cerebral artery, 9 50 years old. a) Pre-operative serial angiography showing the aneurysm; b) severe angiospasm shown, in the post-operative angiogram.

Preliminary observations on the use of nimodipine and Prostaglandine Ei

Fig. 3

395

Patient 61 years 2 , after SAH from a pea-sized aneurysm of the left middle cerebral artery. Pre-operative angiogram.

cared for in a rehabilitation centre. In this case we already applied 5 mg/h. On this patient we tried for the first time the administration of prostaglandine Ei, however, without achieving an improvement of the neurological condition. The second attempt, which we undertook with prostaglandine after onset of spasm in the course of treatment with nimodipine, also failed. Until now we have achieved a single positive result in the treatment with Prostin. A seventy-year-old female patient was admitted with grade III on the Hunt and Hess scale on the day of subarachnoid haemorrhage and was treated with nimodipine. As the severe bleeding blocked the basal cisterns, the patient was operated on the same day. The aneurysm was clipped without difficulty, the blood clots in the basal cisterns and Sylvius' fissure were removed as far as possible and rinsed. Following this, the patient was considerably improved neurologically without any unilateral symptoms and was somnolent. The postoperative angiogram showed a normal vessel tree. Two days later, under the therapy with nimodipine, severe unilateral symptoms followed by coma. Another angiogram performed showed severe spasm especially on the side of the aneurysm. Increase of the dosage of nimodipine to five mg/h yielded

396

Fig. 4

H. P. Ammerer, R. Karnik and G. Perneczky

The same patient as in Fig. 3. a) Severe vasospasm after changing from i.v. nimodipine to oral administration; b) renewed i.v. injection of nimodipine; vascular lumen returns to normal.

Preliminary observations on the use of nimodipine and prostaglandin E,

397

n o clinical improvement. However, a few hours after the onset of treatment with Prostin the neurological condition of the patient improved considerably, and she reacted specifically to painful stimulation without any unilateral symptoms. The next day she was fully conscious and the condition was considerably improved as compared with the time before Prostintherapy. All internal parameters and the ongoing therapy remained unchanged during this time. For the time being we do not wish to overrate these results. The therapeutical success with Prostin is limited even in c o m m o n stroke patients and has not encouraged us too much. The success rate first reported in the literature [1, 2, 3, 4] could not be repeated by us. Perhaps better results could be achieved with Prostacyclin (prostaglandine I2), but we d o not have any experience with it as yet. Finally I would like to present another case, which seems to prove the effectiveness of nimodipine [6, 7] (fig. 3). A 61-year-old female patient was admitted 1 day after a subarachnoid haemorrhage and nimodipine was applied immediately. The patient was in good condition and showed no neurological symptoms besides meningism and severe headache. Angiography revealed a lentil-sized aneurysm of the left A. cerebri media; n o spasm was visible on the angiogram (fig. 3). O n the fifth day after bleeding the condition of the patient was unchanged and operation was performed. The postoperative angiography was without pathological findings, the patient recovered and was without any neurological deficit. Six days after operation the infusion of nimodipine was terminated and oral therapy was started. Already in the evening of that day the patient h a d slight and on the next morning complete m o t o r aphasia and mainly brachial hemiparesis of the right side. Repeat angiography showed unilateral spasm (fig. 4 a), and we immediately administered intravenous nimodipine at a rate of 3 mg/h. 12 hours after the renewed infusion the patient started to move her a r m and h a n d . N o r m a l strength and motor response returned within t w o days. Still another repeat angiography was performed (fig. 4 b). The angiogram obtained was perfectly normal. The patient recovered during her stay in hospital and still showed minimal aphasia on discharge. I nevertheless believe, that in spite of such cases, which are gratifying both to the surgeon and the treating team, we should still wait for the final statistical results of this study.

References [1] Rhodes, R. S. and S. E. Heard: Detrimental effect of high-dose prostaglandin Ei in the treatment of ischaemic ulcers. Surgery 1982, 839. [2] Carlson, L. A. and A. G. Olsson: Intravenous Prostaglandine Ei in severe peripheral vascular disease. Lancet 1, 155-156 (1973).

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H. P. Ammerer, R. Karnik and G. Perneczky

[3] Olsson, A. G. and E. Nilsson: The effect of intravenous prostacyclin on resting pain and healing of ischaemic ulcers in peripheral artery disease. Prostaglandins Med. 6, 3 2 9 - 3 3 9 (1981). [4] Chapleau, C. E. et al.: Cerebral Vasospasm: Effects of Prostaglandin Synthease inhibitions in Vitro. 1980 Congress of Neurological Surgeons. [5] White, R. P. and A. A. Hägen: Cerebrovascular actions of Prostaglandins. Pharm. Ther. Vol. 18, 3 1 3 - 3 3 1 (1982). [6] White, R. P., et al.: Effect of the Calcium Antagonist Nimodypine on contractile Responses of Isolated Canine Basilar Arteries Induced by Serotonin, Prostaglandin, F2 a, Thrombin and Whole Blood. Neurosurgery 10, 3 4 4 - 3 4 7 (1982). [7] Harris, R. I., et al.: The Effects of a calcium Antagonist, Nimodipine, upon Physiological Responses of the cerebral Vasculature and Its Possible Influence upon Focal Cerebral Ischaemia. Stroke 13, 7 5 9 - 7 6 5 (1982).

The use of the Ca-antagonist nimodipine in the prevention and the treatment of clinical ischaemia after subarachnoidal haemorrhage and the value of early aneurysm surgery A. J. M. van der Werf, J. P. Muizelaar, L. M. Hageman, K. W. Albrecht

Introduction After subarachnoidal haemorrhage which in most cases is caused by rupture of a cerebral saccular aneurysm two major complications can occur: 1. recurrent haemorrhage, 2. cerebral ischaemia from vasospasm of one or several cerebral arteries. The first may occur at any time after the first bleeding with a maximum in the second week if the neck of the aneurysm has not yet been occluded by operation. The second complication can be due to many factors among which: trauma to the vessel wall, drop in local blood pressure after rupture of aneurysm, break-down products from blood and or brain tissue. Vaso-constriction is a reversible phenomenon at first, but it may result in a permanent narrowing of the blood vessel once secondary changes in the vessel wall have taken place. In order to contract smooth muscle-fibres composed of actin and myosin clacium is needed. If Ca can be prevented to enter the vessel wall vaso-constriction cannot occur whatever the original spasmogenic agents may be. In the final step of the vaso-constrictive process, the role of calcium is a decisive one. It is therefore logical, that attempts have been made to find a substance, that prevents Ca from entering the vessel wall. One of these substances is nimodipine. A multicentre study on the tolerance and efficacy of nimodipine was set up with Prof. Dr. K. Deck as study director and with thirteen participating centres (table 1). 109 patients (65 women, 44 men) were studied. Tolerance: In all 109 patients side effects could be assessed whereas efficacy in treating ischaemic symptoms could be evaluated in 91 patients. Nimodipine was administered intravenously for 7 to 10 days in a dosage of 12-72 mg per day followed by oral administration of up to 240 mg per day in 34 patients. 45 side effects of nimodipine were seen in 29 out of 109 patients. We found

400 Table 1

A. J. M. van der Werf, J. P. Muizelaar, L. M . Hagemann and K. W. Albrecht Participating centres in the nimodipine trial

Amsterdam Neurochir. Kliniek Acad. Ziekenhuis

Prof. Dr. A. J. M . van der Werf Dr. J. P. Muizelaar K. W. Albrecht L. M. Hageman

Innsbruck

Prof. Dr. V. Grunert Dr. H. Kostron

Neurochir. Universitätsklinik Wien

Prof. Dr. W. Koos Dr. A. Perneczky

Neurochir. Universitätsklinik

Univ.-Doz. Dr. L. Auer

Graz Universitätsklinik für Neurochirurgie

Prof. Dr. W. J. Bock Dr. H. K. Seibert

Düsseldorf

PD Dr. M . Gaab

Neurochir. Universitätsklinik Würzburg Neurochir. Poliklinik der Klinik Universität, und Würzburg Bonn Neurochir. Universitätsklinik

Prof. Dr. R. Wüllenweber Dr. D. K. Boker Prof. Dr. E. Kazner Dr. Ch. Sprung

Berlin Prof. Dr. G. Meinig Klinikum Westend - Neurochirurgie Mainz Neurochir. Klinik

Dr. U. Fuhrmeister

der Johannes-Gutenberg-Universität Würzburg

Prof. Dr. E. Grote

Neurologische Universitätsklinik Dr. H. Jaksche Gießen Zentrum für Neurochirurgie der Justus-Liebig-Universität Homburg/Saar Neurochir. Universitätsklinik Neurochir. Essen Universitätsklinik

Dr. H. M. Mehdorn

The use of the Ca-antagonist nimodipine in the prevention

401

the following complications: Cardiac rhythm-disturbances, hypotension, GOT, GPT and gamma GT changes. Most of these can also be found in the natural history of a SAH. Interaction with other drugs was only found with propranolol. We may conclude from this tolerance study that side effects were rare, never serious in nature and that they seldom necessitated interruption of treatment.

Treatment The other part of the study was concerned with the treatment of ischaemic neurological deficits following nimodipine. 91 patients were assessed. Sixty of them showed clinical signs of ischaemia preoperatively and 31 postoperatively. 84% of the patients were in clinical grade III at the start of the treatment. The administration of nimodipine began less than 24 hours after the onset of clinical ischaemia in 67% of the patients, between 24 and 48 hours in 12% and later than 48 hours in 21% of the patients (table 2). Complete recovery from clinical ischaemia at the end of the treatment was found in 59 of the 91 patients (65%). 16 patients died: 10 died from vasospasm alone (11%), 6 patients died from recurrent haemorrhage or from an unrelated cause (table 3). Clinical improvement was found in 69% of the 61 patients treated with nimodipine within 24 hours after the onset of ischaemic signs as against 53% of the 19 patients in whom the administration started more than 48 hours after the first symptoms of cerebral ischaemia. Although the difference is not great, early treatment seems to give the best results.

Prevention Nevertheless treatment of clinical ischaemia may often come too late. Prevention should therefore be preferred. A number of neurosurgical centres of Western Europe undertook a double-blind randomised study with prophylactic administration of nimodipine or placebo administered within 3 days after SAH. The drug was given intravenously in a dosage of 1 - 2 mg per hour. Table 2

Ischaemic neurological deficit

6 0 patients preoperatively 31 patients postoperatively 8 4 % of patients were in grade III at the start of the treatment: < 2 4 hrs after onset in 6 7 % 2 4 to 48 hrs in 1 2 % > 4 8 hrs in 2 1 %

402 Table 3

A. J . M . van der Werf, J. P. Muizelaar, L. M . H a g e m a n n and K. W. Albrecht Treatment of clinical ischaemia with nimodipine

Complete recovery at the end of treatment in 5 9 out of the 91 patients ( 6 5 % ) 16 patients died: 10 died from v a s o s p a s m alone ( 1 1 % ) 6 patients died from recurrent haemorrhage or from an unrelated cause

Unfortunately this study could not be completed because a number of centres withdrew judging it to be unethical to withhold nimodipine from their patients. Furthermore after a similar study by Alan et al. with an orally administered drug was completed at the end of 1982 and published in March 1983, it was decided to stop this double-blind study. Alan and coworkers [1] found severe ischaemia in 8 cases of the placebo group versus only one case in the nimodipine group. Slight and moderate ischaemia however were found more frequently among the nimodipine treated patients. The time interval between the haemorrhage, angiography and surgery is not mentioned in their paper.

Early surgery In 1979 we started operating on aneurysms early within 3 days after the bleeding. This policy showed not only a dramatic drop in recurrent bleeding but also a decrease in severe hitherto often lethal clinical ischaemia. We believe that a careful removal of blood and fibrin clot from the cisterns together with hypervolemia, decreased viscocity of the blood by rheomacrodex and mannitol and last but not least induced hypertension have contributed to a more favourable outcome in the overall management of the SAH patient. Early surgery was undertaken in 57 patients since 1979, all in grade 1 - 3 and operated within 72 hours after the haemorrhage. Angiographic spasm occurred in 50% and clinical ischaemia was found in 34% of the patients. Two patients died as a result of clinical ischaemia and severe cerebral infarction. Good or excellent results were obtained in 84% of the patients (table 4). Table 4

Cerebral aneurysm - early surgery (n = 57), < 7 2 hours after S A H , grade I—III

pre-operative spasm

4

post-operative spasm

24

clinical ischaemia

18

J

>50% 34%

outcome: death related to v a s o s p a s m

2

death due to other causes

3

moderate disability

4

good excellent

5 43

J

>84%

The use of the Ca-antagonist nimodipine in the prevention Table 5

403

Double blind prophylactic administration of nimodipine

19 patients - operated day 1 - 1 5 (80% < 72 hours) Botterell-grade I or II 17 patients grade III 1 patient grade IV 1 patient

Shortly after this time we started our participation of the double-blind randomised placebo-controlled preventive nimodipine study. Our material consisted of 19 patients, operated on day 1 to 15. 80% were operated within 72 hours after the haemorrhage. 17 patients were in grade 1 or 2, 1 patient in grade 3 and one in grade 4 (table 5). Clinical ischaemia was found in 5 patients (26%) and angiographic spasm in 6 patients (30%). The outcome was excellent in 17 patients (90%). One patient died (because of wrong position of the clip). One patient remained severely disabled after a recurrent haemorrhage (from a second aneurysm). In tables 6 and 7 the results of early surgery alone can be compared with those of early surgery plus nimodipine or placebo. Though the nimodipine-trial series were small the incidence of clinical ischaemia and that of good or excellent outcome is very much the same in both series: 27%—33% and 87%—83% respectively. Death related to vasospasm was confined to the early surgery group.

Discussion Do we have any sign or symptom capable of predicting which particular patient is likely to develop severe vasospasm and clinical ischaemia? From the work of Fischer, Adams, Mizukami, et al. [2, 4, 5] and from our own experience we know that patients with blood filled basal cisterns or the spaces of the Sylvian fissure seen in the CT-scan made soon after the SAH are a high risk in developing severe ischaemia. We therefore recommend giving these patients nimodipine prophylactically and to operate them early. We keep the blood pressure slightly above normal, increase the amount of fluid to 3 L per day and add rheomacrodex and mannitol to decrease the blood viscocity [3]. If clinical signs of ischaemia develop the blood pressure is raised by 20% with continuous intravenous administration of phenylephrine. Table 6

Early surgery - nimodipine trial (n = 15), < 72 hours after SAH, grade I—III

clinical ischaemia outcome: death related to vasospasm excellent or good

4

(27%)

0 13

(87%)

404

A. J . M . van der Werf, J . P. Muizelaar, L. M . Hagemann and K. W. Albrecht

Table 7

Early surgery - no nimodipine (n = 42), < 7 2 hours after SAH, grade I—III

clinical ischaemia outcome: death related to vasospasm excellent or good

14

(33%)

2

( 5%) (83%)

35

Conclusions 1. The Calcium-antagonist nimodipine is a safe drug. Side effects are minimal both after intravenous and oral administration. 2. The application of results in an nimodipine improvement of ischaemic symptoms caused by SAH should be administered very early after their onset. 3. Nimodipine administration after early aneurysm-surgery in SAH does not seem to be more efficient in preventing clinical ischaemia than early surgery only. 4 . Nevertheless, when the CT-scan shows blood filled basal cisterns or the Sylvian fissure full of blood, we recommend to have early surgery followed by the administration of nimodipine. 5. If in spite of these measures clinical ischaemia does occur, we advocate the use of induced hypertension and an improvement of blood rheology.

References [1] Alan, G., et al.: Cerebral Arterial Spasm. A controlled Trial of Nimodipine in patients with subarachnoid Haemorrhage. New Engl. J . Med. 3 0 8 , 6 1 9 (1983). [2] Fischer, C. M . , et al.: Relation of cerebral vasospasm to subarachnoid haemorrhage visualized by computerized tomographic scanning. Neurosurgery 6, 1 (1980). [3] Muizelaar, J . P., P. W. Enoch, A. K. Hermes and D. P. Becker: Mannitol causes compensatory cerebral vasoconstriction and vasodilation in response to blood viscosity changes. J . Neurosurg. 5 9 , 8 2 2 - 8 2 9 (1983). [4] Adams, H. P., et al.: C T and clinical correlations in recent aneurysmal subarachnoid haemorrhage. A preliminary report of the Cooperative Aneurysm Study. Neurology 3 3 , 9 8 1 (1983). [5] Mizukami M . , et al.: Value of computed tomography in the prediction of cerebral vasospasm after aneurysm rupture. Neurosurgery 7, 5 8 3 (1980).

A trial with nimodipine, a calcium entry blocker for the prevention and treatment of ischaemic brain damage H. J . Gelmers

Introduction The neurological status of a patient, having a subarachnoid haemorrhage, influences both the mortality rate and the manner of survival. Amongst the complicating factors, influencing the neurological status, vasospasm is of major importance. However, while some clinicians remain unconcerned about its importance [14,16], there are many reports that morbidity and mortality rise sharply when vasospasm accompanies subarachnoid haemorrhage [3, 15, 17, 21]. It has been suggested that, if vasospasm produces a further neurological disorder, it is probably caused by the reduction of cerebral blood flow [10]. It is also known that cerebral infarction is commonly found in these patients [18, 20]. Nimodipine described as a new calcium entry blocker, with a preferential effect on brain vessels, preventing spasm of the isolated rabbit basilar artery, produced both by depolarization and receptor stimulation [11]. Experiments have shown that nimodipine can prevents post-ischaemic impairment of cerebral perfusion [7,12]. This may be a major factor in the causation of neuronal lesions [1, 19,]. In patients with ischaemic deficits the effects of an intravenous single dose nimodipine were studied by rCBF measurements using the xenon-133 injection technique. A dose dependent increase of hemispheric blood flow was found. In some patients an inverse steal phenomenon was observed, but in no instances an intracerebral steal phenomenon. These reports provided the stimulus for clinical studies in order to establish, whether treatment with nimodipine would reduce neurological disorders caused by a ischaemic neuronal damage.

406

H.J.Gelmers

Methodology Organization The study limited to one center was carried out over a period of 11 months. Patients over 40 years of age and from either sex were included treated and followed up at the same Hospital. All patients who were incorporated in this study were recorded within 24-48 hours after the onset of neurological symptoms.

Patients and methods Sixty patients with an acute ischaemic stroke were used in the study. The initial diagnosis was confirmed by a thorough neurological examination. All patients were scored on the basis of their neurological status using a patient evaluation sheet according to Mathew et al. [13], modified in some minor detail [4], The efficacy of nimodipine was assessed entirely in terms of the changes in the Mathew scale on days 1 , 2 , 3 , 5 , 7 , 1 4 , 2 1 and 28. After admission to the hospital and inclusion into this study the patients were randomized into either a control or a nimodipine group in a single blind choice. All patients received a standard treatment comprising 10% depolymerized dextran for 12 hours during five days (controlgroup). In the treatment-group 120 mg nimodipine was given in three divided doses. Digitalis, antihypertensive medication and antibiotics were administered as required. A low dose of subcutaneous heparin (10 000 I E in two divided doses) was given to prevent of deep vein thrombosis in the legs [5], Both groups received the same good nursing, medical care and rehabilitation. Cerebral vasodilators, steroids and hyperosmolar agents were avoided. Nimodipine was administered to dysphagic patients via a naso-gastric tube. Data analysis Both groups were compared for various variables using a simple analysis of variance. The differences between the pre- and post-treatment values were ascertained for each patient and a 3-factor partial hierarchal variance analysis performed. The individual items of the Mathew scale were tested separately for each treatment period using the Wilcoxon-U-test; the executing probability was tested according to Bonferoni-Holm [8]. The frequency table for the evaluation of the global assessment was evaluated by means of the chi-square test. The choise of patients All patients with the sudden onset of a focal neurological disorder between 24—48 hours prior to admission were included. Subarachnoid haemorrhage was excluded

A trial with nimodipine, a calcium entry blocker

407

by sampling cerebrospinal fluid. Mild xanthochromic liquor was excepted in patients in whom cardiac embolism was the cause of ischaemic stroke. In all these patients CT-scans confirmed the final diagnosis. Since rational treatment of cerebral haemorrhage would be different from the treatment of cerebral infarction in all patients in whom it was doubtful to distinguish between cerebral haemorrhage and cerebral infarction, computerized tomography was used (n = 26). Therefore, patients with cerebral haemorrhage or with lacunar infarction in the internal capsule or the brain stem were excluded, and only patients with major vessel occlusion of the hemisphere were included.

Results Comparability of treatment groups Sixty patients were admitted to the trial of which 31 entered the control-group, while 29 entered the treatment-group. Table 1 shows the distribution of patient characteristics in both groups. The differences between the groups tended to be small. Table 1

Distribution of patient characteristics after randomization standard group

test group

number of patients

31

29

age (mean ± female

68,6 ±

S.D.)

male

10,9

69,6 ±

16

11

15

18

11,2

Stroke type total left

17

16

ICAO

7

4

ACAO

2

2

MCAO

7

9

PCAO

1

2

14

13

total right ICAO

2

4

ACAO

-

-

MCAO

10

7

PCAO

2

2

risk factors hypertension

8

9

diabetes mellitus

2

cardiac arythmia

3 2

heart failure

5

2

pulmonary dysfunction

3

2

1

I C A O = internal carotid artery occlusion, A C A O = anterior cerebral artery occlusion, M C A O = middle cerebral artery occlusion, P C A O = posterior cerebral artery occlusion.

408

H.J.Gelmers

Except for minor differences in heart rate and serum levels for sodium and potassium both groups were comparable.

Neurological outcome In both groups some patients died before completion of the study. Their data and stroke scores are summarized in table 2. There was a highly significant difference (p < 0.0001), between the pre- and posttreatment total scores for both therapy and time, over 1 - 4 weeks of treatment (fig. 1). This suggests a better recovery of neurological function in the nimodipine-group. This was also reflected in the mean values of the differences after the first week of treatment. Means of the differences for nimodipine which were 20.8 in the first week and increased to 2 5 . 3 , 2 6 . 9 and finally 27.7 points. The corresponding values under standard therapy were 1 0 . 3 , 1 3 . 4 , 1 5 . 1 and 15.5 in the 1st, 2nd, 3rd and 4th week respectively. Upon subjecting individual items in the Mathew scale to a non-parametric analysis significant differences were found in level, of consciousness on the 3rd and 5th day of treatment and in performance or disability after the first week of treatment (tab. 2). This is of clinical relevance, as prolonged unconsciousness reduces the patient's chance of survival. From the first week to the end of treatment (day 28) the average values for better performance or disability improved to a highly significant extent (p < 0.0004) when compared to the standard therapy-group. Two deaths occurred in the nimodipinegroup, and six in the standard therapy : group. It appears likely that the trend for a lower mortality rate seen in the nimodipine-group, is due to a greater tendency for recovery. Table 2 Age

Data and stroke scores of patients who died before completion of the study Sex

Presumed cause

Cause of

Day

Neurologic score on day

of stroke

death

of

0,

1,

2,

3,

5,

7,

14, 21, 28

death Standard group 69

F

cardiac arythmia pneumonia

6

61

59

57

51

49

-

-

71

M

cardiac arythmia pneumonia

18

59

57

58

58

58

53

53

78

F

ICAO

pneumonia

10

36

34

33

33

33

33

74

F

MCAO

pneumonia

9

58

58

58

56

55

55

_ _ _ _ _ _

67

M

MCAO

reinfarction

12

46

46

46

45

30

26

—

9

54

54 54

54

56

61

_ _ _

18

49

49

57

67

72

-

-

—

—

(cerebral) Test group 87

F

MCAO

reinfarction (cerebral)

83

F

MCAO

reinfarction (cerebral)

ICAO = internal carotid artery occlusion MCAO = middle cerebral artery occlusion

53

72

-

-

A trial with nimodipine, a calcium entry blocker

409

Neurological score (Mathew) (means ± standard deviation) 90 - i neurological score

nimodipine

//

placebo

—

r~

12 Fig. 1

I

16

—I

20

1

24

1

28 Day

Neurological score (Mathew-scale) in patients with acute ischaemic stroke, treated with nimodipine during 28 days, versus a standard regimen (mean values ± S.D.).

Side effects During the first three days of treatment two patients developed mild abdominal cramps. Detailed physical and radiological examination of the abdomen, urinanalysis, haematology and biochemistry were all normal. The patients were under no medication which could have caused these side effects. Bedridden stroke patients are prone to constipation which may in itself give rise to mild lower abdominal discomfort. Despite routine administration of a lubricant purgative from the time of admission, it was not possible to assure adequate bowel function in all patients. Since nimodipine has a musculotrophic action it may have caused intestinal relaxation with subsequent constipation as the result. A 36-year old right handed man enrolled in the treatment-group, developed a confusional state. He was admitted after developing an acute paralysis of the left leg and a mild paresis of the left arm. In addition, there was a left-sided homonymous hemianopia with some deviation of the eyes. Neurological examination revealed no further abnormalities. A CT-scan (4th day) showed a triangular shaped hypodens area in the occipital region, which was diagnosed as an infarction in the territory of the right posterior cerebral artery, probably of embolic origin. Although psychotic reaction after stroke are unusual, it is well

410

H . J. Gelmers

known that infarction of the inferomedial surface of the occipital lobe may produce agitated delirium and visual hallucinations [9]. Nevertheless, the possibility of a causative relationship between the psychotic behaviour and nimodipine treatment cannot be ruled out completely.

Discussion After considering the pharmacology of nimodipine [7, 11, 12], preliminary rCBF data [6] and the absence of any alternative rational therapy, a single blind trial to test the efficacy of nimodipine for the treatment of postischaemic neurological deficits seems justified. Although there is some insufficiency in all scoring systems we used to evaluate the outcome in stroke trials [2], the Mathew scale, largely based on traditional clinical examination, correlated well with the initial severity as with the outcome [13]. The total score after four weeks of nimodipine therapy was significantly higher than that for the standard therapy alone. This means, that neurological symptoms as measured by the Mathew total score, improved more rapidly with nimodipine than with standard therapy. Examination of individual items of the Mathew scale showed that nimodipine causes a particularly marked improvement in the level of consciousness after the first week of treatment. A significant easing of disability, in comparison to standard therapy, is seen with nimodipine after the first treatment week. Clinically significant differences of blood pressure were not observed. The drop in pulse rate, seen under nimodipine treatment, is attributable to the significantly elevated pretreatment values in this group. The diminution of pulse rate was in no instance of clinically significance. There is no reason to assume that the pathophysiology of brain ischaemia and related symptoms, such as post-ischaemic vascular reactivity in subarachnoid haemorrhage, is basically different from that in stroke. Nimodipine appears to be very promising for the treatment of patients with ischaemic stroke. We conclude from this clinical trial that nimodipine can be of therapeutic value in the management of subarachnoid haemorrhage. We hope that further studies will give further support to our findings.

References [1] Bleyaert, A. L., E. M . N e m o t o , P. Sofar et al.: Thiopental amelioration of brain d a m a g e after global ischaemia in monkeys. A n e s t h e s i o l o g y 4 9 , 3 9 0 - 3 9 8 (1978). [2] Cupildeo, R., S. Habermann and F. C. Rose: Stroke trials — the facts. In: F. C. Rose, ed.: Advances in stroke therapy, pp. 53—62. Raven Press, N e w York 1982.

A trial with nimodipine, a calcium entry blocker

411

[3] Fischer, C. M., G. H. Roberson and R. G. Ojemann: Cerebral vasospasm with ruptured saccular aneurysm - the clinical manifestations. Neurosurgery 1, 2 4 5 - 2 4 8 (1977). [4] Gelmers, H. J.: Effect of glycerol treatment on the natural history of acute cerebral infarction. Clin. Neurol. Neurosurg. 78, 2 7 7 - 2 8 2 (1975). [5] Gelmers, H. J.: Effects of low-dose subcutaneous heparin on the occurrence of deep vein thrombosis is patients with ischaemic stroke. Acta Neurol. Scandinav. 61, 3 1 3 - 3 1 8 (1980). [6] Gelmers, H . J.: Effect of nimodipine on postischaemic cerebrovascular reactivity as revealed by measuring regional cerebral blood flow. Acta Neurochirurgica 63, 2 8 3 - 2 9 0 (1982). [7] Hoffmeister, F., A. P. Krause and S. Kazda: Influence of nimodipine on the postischaemic changes of brain function. Act. Neurol. Scan. 60 (Suppl. 72). 3 5 8 - 3 5 9 (1979). [8] Holm, S. A.: A simple sequentially rejective multiple test procedure. Scand. Statist. 6, 65—75 (1979). [9] Horenstein, S., W. Chamberlain and J. Conomay: Infarction of the fusiform and calcarine regions: agitated delirium and hemianopsia. Trans. Am. Neurol. Ass. 90, 8 5 - 8 9 (1967). [10] Ishii, R.: Regional cerebral blood flow in patients with ruptured intracranial aneurysms. J. Neurosurg. 50, 5 8 7 - 5 9 4 (1979). [11] Kazda, S. and R. Towart: Nimodipine: a new calcium antagonistic drug with a preferential cerebrovascular action. Acta Neurochirurgica 63, 2 5 9 - 2 6 5 (1982). [12] Kazda, S., B. Garthoff, H. P. Krause et al.: Cerebrovascular effects of the calcium antagonistic dihydropyridine derivate nimodipine in animal experiments. Drug. Res. 32 (I), 4, 331—338 (1982). [13] Mathew, N. T., J. S. Meyer and V. H. Rivera: Double blind evaluation of glycerol treatment in acute cerebral infarction. Lancet II, 1327-1333 (1972). [14] Millikan, C. H.: Cerebral vasospasm and ruptured intracranial aneurysm Arch. Neurol. 32, 4 3 3 - 4 4 9 (1975). [15] Nibbelink, D. W., A. L. Saks and A. L. Knowler: Antihypertensive and antifibrinolytic medications in SAH and their relation to cerebral vasospasm. In: R. R. Smith, J. T. Robertson (eds.). Subarachnoid haemorrhage and cerebrovascular spasm, pp. 177—205. Charles C. Thomas, Springfield/Ill. 1975. [16] Ojemann, G. A. and E. S. Flamm: Summary of panels on subarachnoid haemorrhage and cerebral aneurysms. Clin. Neurosurg. 24, 2 4 8 - 2 5 3 (1977). [17] Post, K. D., E. S. Flamm, A. Goodgold et al.: Ruptured intracranial aneurysms. Case morbidity and mortality. J. Neurosurg. 51, 4 6 6 ^ 7 5 (1977). [18] Schneck, S. A. and I. I. Kricheff: Intracranial aneurysm rupture, vasospasm and infarction. Arch. Neurol. 11, 6 6 8 - 6 8 0 (1964). [19] Siesjo, B. K.: Brain energy metabolism. John Wiley, New York 1978. [20] Stern, W. E.: Mechanisms in the production of hemiparesis associated with intracranial aneurysm. Brain 78, 5 0 3 - 5 1 3 (1955). [21] Sundt, T. M . jr.: Management of ischaemic complications after subarachnoid haemorrhage. J. Neurosurg. 43, 4 1 8 - 4 2 5 (1975).

Nimodipine in prevention and treatment of cerebral vasospasm after SAH L. Russegger, H. Kostron, V. Grunert

Introduction The technical problems in aneurysm surgery seem to be solved largely, while the timing of operation and management of cerebral vasospasm have become the main problems in SAH following ruptured aneurysms. The pharmacological concept of cerebro-selective calcium antagonism of nimodipine appears to provide a beneficial effect for preventing and treating arterial vasospasm. For this reason we have investigated the usefullness of this drug in clinical practice.

Patients and methods 50 patients with SAH from a ruptured aneurysm (33 of the anterior communicating artery, 8 of the internal carotid artery, 7 of the middle cerebral artery, 2 of the posterior communicating artery) were operated upon and treated with nimodipine. At admission, at beginning, and at end of the treatment the patients were examined neurologically and classified according to the scale of Hunt and Hess [1]. As we aimed at a uniform grading we used this scale also post-operatively. It has to be. mentioned that we graded differences of reflexes, discret hemiparesis as well as a mild psycho-organic syndrome at the end of the treatment into grade II, moderate hemiparesis and/or a manifest psycho-organic syndrome into grade III (see tab. 1). Nimodipine was given as a 0.02% solution by intravenous drip in a dosage of 48 mg daily for up to 10 days followed by oral administration up to 360 mg per day for 3—4 days. In 5 cases the drug was administered locally. In 38 patients nimodipine was given when clinical manifestations of spasm were present whereas 12 patients were pre-treated to prevent these symptoms. Before and after the treatment CT-scan and angiograms were carried out and compared with the clinical symptomatology. No control angiograms were available in 6 cases of the prophylaxis-group. Each patient underwent the standard laboratory investigations. On admission the patients received dexamethasone, phenytoine, hydergine and cimetidine as well as epsilon-amino-capric-acid and aprotinine.

414

L. Russegger, H . Kostron and V. Grunert

Table 1

I:

Grading (Hunt and Hess) of the neurological status after S A H

Scale of Hunt and Hess

Completion for final evaluation

Asymptomatic bleeding or minimal head-

complete recovery, no neurological deficit

ache, discret meningism II:

moderate to severe headache, meningism,

differences of reflexes or discret hemiparesis,

no neurological deficit except brain nerve

mild psycho-organic syndrome

disturbances III: IV:

apathia, disorientation or focal neurological

moderate hemiparesis and/or manifest psy-

deficits

cho-organic syndrome

stupor, moderate to severe hemiparesis, beginning decerebration rigidity, vegetative disturbances

V:

coma, decerebration rigidity

Results Therapy-group Out of 38 patients 31 were in grade I or II according to Hunt and Hess at admission ( = 80%). At the beginning of the treatment with nimodipine 9 patients ( = 24%) were still in these favourable grades, but 56% had been deteriorated into the unfavourable grades III and IV. At the end of the treatment 36% had improved again, so that 60% reached finally grade I and II, 32% grade III and IV. 3 patients who were excluded from the final result died and recorded seperatly (see tab. 2). To prove a possible beneficial effect of nimodipine we examined the final results from different points of view. Those patients which had had spasm and were treated already before surgery improved from a mean grade of Hunt and Hess of 3 to 1.5. This group who showed clinical signs of spasm post-operatively and was treated afterwards improved from 2.9 to 2.2. The improvement however was only from 2.9 to 2.6 in the group with pre-operative existing spasm and post-operatively administered nimodipine. In those 23 patients showing final grades I or II spasm appeared in 11 cases preoperatively on day 1—6 after SAH (mean day 3, day of SAH = day 0). Surgery was performed on day 3—14 (mean day 8). Spasm occurred 12 times post-operatively within 4—48 hours (mean 15 hours). In these cases surgery was performed on day 3 - 1 7 (mean day 8). In 12 patients who reached finally the grades III and IV spasm appeared 5 times pre-operatively on day 2—7 after SAH (mean day 4) and surgery was performed on

Nimodipine in prevention and treatment of cerebral vasospasm Table 2

415

Symptomatology of patients treated by nimodipine at the admission, the beginning and the end of treatment

Hunt and Hess

beginning of treat-

admission

end of treatment

ment grade I

8

0 = 80%

grade II

5 = 24%

23

18

56%

grade III

= 60%

9

6

36%

25 = 20%

9 = 76%

= 32%

grade IV

1

4

3

grade V

0

0

3 + = 8%

day 6—26 (mean day 14). 7 times spasm was evident post-operatively within 1—48 hours (mean 20 hours). Surgery was performed on day 4—9 (mean day 5). The interval from the onset of spasm to the beginning of the treatment with nimodipine was up to 48 hours in 20 cases. These patients were finally graded I and II. In 3 cases of this group the treatment began on day 5 - 8 after appearance of spasm. In these patients with the final grades III and IV the treatment was begun within 48 hours after occurrence of clinical spasm, in 4 cases on day 3 - 2 6 . The mean time of onset to the treatment of the spasm was in the first group 10 hours and in the latter group 24 hours. The average distribution of sex and age in the final grading can be seen from table 3. CT-Scan and angiographic findings at the beginning and at the end of treatment are shown in table 4. As mentioned above 2 patients of the therapy-group were excluded from the final resume because of operative complications. The third case will be discussed seperatly and fully because of a possible severe side effect from this kind of treatment. Table 3

Age and sex distribution

final outcome

grade I

grade II

grade III

grade IV

4 1 a (n = 4) 4 0 a (n = 1)

45 a (n =

5 6 a (n = 3) 5 2 a (n = 6)

33 a (n = 1) 5 6 a (n = 2)

mean age male female

7) 49 a (n = 11)

sex distribution male

73%

27%

female

60%

40%

416 Table 4

L. Russegger, H. Kostron and V. Grunert CT-scan and angiographic findings

final outcome

grade I ( n = 5)

grade II 1:n = 18)

grade III (n =

grade IV (n = 3)

9)

CT

XB

XE

XB

XE

XB

XE

XB

XE

no oedema focal oedema diffuse oedema

3 2 0

5 0 0

10 8 0

14 4 0

2 7 0

3 4 2

0 3 0

0 2 1

4 1 0

3 2 0

9 6 3

3 13 2

6 3 0

1 7 1

3 0 0

0 3 0

angiogram no spasm local spasm generalized

XB = beginning of treatment, X E = end of treatment

Prophylaxis-group The treatment protocol for this group excluded other grades than I and II. The beginning of treatment with nimodipine was on day 1—4 after SAH (mean day 2, 3). Surgery was performed on day 2—7 (mean day 4). The mean time period from the beginning of the treatment to surgery was 40 hours. The grading, CT-scan and angiographic findings of these patients are listed in table 5.

Discussion The present study provides the following informations: 1. Our results confirm the assumption that nimodipine has a prophylactic effect concerning the final outcome of the patients by enabling earlier surgery and possibly a higher tolerance for operating. Application of nimodipine should be pre-operatively. Our experience with topically administered nimodipine in the 5 cases is to limited for drawing conclusions. 2. As far as late surgery is concerned our results indicate that on the average up to day 8 seems to be most favourable. Indeed, our best results were in the prophylaxisgroup where patients were operated on mean day 4 but treated with nimodipine pre-operatively in the grades I and II. 3. The intervall between the onset of clinical spasm end the beginning of treatment is of great importance. The satisfactory results indicate that the treatment of vasospasm should be started as early as possible. 4. The fate of patients after spontaneous SAH is different in the various age and sex groups but may be uncorrelated to nimodipine treatment. Table 3 shows that 73% of

Nimodipine in prevention and treatment of cerebral vasospasm Table5

417

Prophylaxis group (n = 12)

Hunt and Hess

beginning of treatment

grade grade grade grade

3 9 0 0

8 3 1 0

7 5 0

10 2 0

I II III IV

end of treatment

721scan no oedema focal oedema diffuse oedema angiogram no spasm local spasm generalized spasm

9 3 0

3 3 6 X no control angiogram

our male patients registrated in the therapy-group improved to grade I or II, but only 60% of female patients did so. The older the patients were, the worse were their later neurological conditions. 5. CT-scan findings improved in those patients which were ranged finally in the grades I and II but deteriorated significantly in patients graded III and IV at the end of the treatment. In all groups local spasm was more often seen in later angiograms than in the first investigation. This occurred despite the fact, that most of the patients had improved. There was no clear correlation between angiographic spasm and neurological manifestations [2, 3], posing the question if a cerebral angiospasm is the only limiting factor in good recovery or if other still unknown complicating circumstances after SAH exist. It is important to state that none of our 50 patients resisted treatment. As a regular side effect we saw a moderate decrease of the systolic blood pressuce and in some cases a slight increase of the liver tests parameters. The impressions was gained that nomodipine could increase a manifest brain oedema as seen in one patient whom we excluded from the final evaluation: A 46-years old female patient suffering from an aneurysm of the anterior communicating artery was operated successfully and immediate postoperative nomodipine treatment followed. The primary CT-scan showed no brain oedema, the angiogram revealed no vascular spasm (see fig. 2 a). On the 3rd post-operative day a left hemiparesis and an increasing loss of consciousness occurred, the condition worsened until the patient, died on the 14th day. No additional treatment reduced the severe increase in intracranial pressure. Figures 1 and 2 b shows CT-scan and angiogram of the 12th day.

418

Fig. 1

L. Russegger, H. Kostron and V. Grunert

CT-scan of 46-years old female patient performed on the 12th day after successful clipping of an ACA-aneurysm. Nimodipine was applied immediately postoperatively.

Conclusion For starting the treatment with nimodipine day 1 - 4 after SAH and day 4 for surgery has proved to be favourable. Our results indicate the value of nimodipine treatment in preventing the clinical manifestations of cerebral spasm, however this beneficial effect was not seen after onset and manifestation of spasm. We have to be cautious and aware of possible side effects of the nimodipine treatment such as increase of brain oedema and increase of membrane susceptibility to metabolic toxins.

Summary In 50 patients with SAH from a ruptured aneurysm surgery and treatment with nimodipine was performed. In 38 cases nimodipine was applied at clinical manifestations of spasm, 12 patients were pretreated to prevent this manifestations. The drug was administered as a 0.02% solution by an intravenous drip in a dosage of

Nimodipine in prevention and treatment of cerebral vasospasm

Fig. 2

419

Patient from fig. 1. a) preoperative angiogram, b) severe spasm in re-angiography at day 12.

48 mg daily for up to 10 days followed by oral application up to 360 mg per day for 3—4 days. The study shows that nimodipine should be applied pre-operatively because it seems to have a prophylactic effect concerning the final outcome for the patients by providing a possible higher tolerance for the operation. In therapeutic cases the time period from onset of the clinical spasm until beginning of the treatment with nimodipine should be as short as possible. Day 1 - 4 after SAH for the beginning of the treatment and day 4 for surgery have been proved as most favourable in this study. We have to be aware of possible side effects of this treatment such as an increase of a manifest brain oedema.

References [1] Hunt, W. and R. M. Hess: Surgical Risk as Related to Time of Intervention in the Repair of Intracranial Aneurysms. J. Neurosurg. 28, 14-19 (1968). [2] Russegger, L., H. Kostron, K. Twerdy und V. Grunert: Klinische Erfahrungen mit Nimodipin (Bay e 9736). Neurochirurgia, in press (1983). [3] Schneck S. A. and I. Kricheff: Intracranial Aneurysmrupture, Vasospasm and Infarction. Arch. Neurol. (Chicago) 11, 6 6 8 - 6 8 0 (1964).

Tolerance of temporary arterial occlusion in early aneurysm surgery"* B. Ljunggren, H. Sâveland, L. Brandt

Introduction Intra-operative aneurysmal rupture or technical difficulties with aneurysm neck delineation may necessitate a protracted arterial occlusion [17, 21, 28, 29]. It has been claimed, mainly from studies by Suzuki and coworkers, that temporary occlusion of the anterior cerebral artery (A-l), the internal carotid artery (ICA), and the middle cerebral artery (MCA) may be tolerated for at least 20 minutes without neurological sequelae [23, 24, 28, 29]. In the last years there has been a resurgence in aneurysm surgery carried out without delay after subarachnoid haemorrhage (SAH) [15—19, 25]. At present there is, however, scanty information available on the possible tolerance of temporary arterial clipping during aneurysm operations performed in the acute stage, i.e. within the first days after SAH [17, 19]. Cerebral ischaemia hampers intracellular calcium homeostasis resulting in a rise of free intracellular calcium. This may lead to further deterioration of mitochondrial function and membrane integrity and ultimately to irreversible neuronal damage. At present there is experimental evidence that calcium entry blockers may be potentially beneficial in the management of cerebral ischaemia in general and cerebral vasospasm in particular [1—3, 5—11, 22, 27]. Temporary occlusion in the acute stage after aneurysm rupture of a major artery supplying the brain involves a risk of immediate focal ischaemia that may lead to permanent neurological deficit and may also aggravate late cerebral vasospasm or delayed cerebral ischaemic dysfunction. In the present study patients subjected to temporary arterial occlusion in the acute stage after aneurysmal SAH were examined retrospectively for the occurence of immediate or late focal ischaemia and for a possible anti-ischaemic effect of the calcium entry blocker nimodipine.

* This study is dedicated to the meccenates of vasospasm research in Lund: Einar Bjorkelund's Foundation, Elsa and Thorsten Segerfalk's Foundation and Elsa Schmitz's Foundation.

422

P. Ljunggren, H. Saveland and L. Brandt

Patients and methods The study includes 2 6 non-diabetic patients, who were operated upon for a ruptured supra-tentorial aneurysm and who were subjected to tempof^ry arterial clipping. Twenty-three of the patients were operated upon within 3 days after SAH, and three patients underwent operation on day 5 after SAH. Eighteen patients had a ruptured MCA aneurysm and 8 had a ruptured anterior communicating artery (ACoA) aneurysm. Immediately prior to the operation 8 patients were considered to be in Hunt and Hess [14] neurological grade I, another 8 patients in grade II, seven patients in grade II, and one patient in grade IV. The grade III patients had Glasgow coma scale scores between 12 and 14. The grade IV patient had 10 GCS scores and was in grade IV b according to the modified grading system proposed by Teasdale et al. [26]. The reason for the use of a temporary clip was pre-mature aneurysm rupture in 9 MCA aneurysm patients and 5 patients with ruptured ACoA aneurysms. In 9 patients temporary clips were applied in order to facilitate dissection of the aneurysm. In three patients temporary occlusion of the MCA was found to be a prerequisite to allow proper clipping of large or giant, broad-based aneurysms. The temporary arterial occlusion was achieved by a Sugita clip in one patient, by Heifetz clips in five patients, and in the other 2 0 patients by the use of different standard Yasargil clips. The occlusion time varied from 4V2 min to 48 minutes. All patients were operated upon via a standard pterional flap. They were premedicated with diazepam (10 mg rectally) and prior to induction anaesthesia, fentanyl (0.005 mg/kg of body weight) was given for analgesia, supplemented by pancuronium bromide (Pavulon; Organon Pharamaceuticals, West Orange, New Jersey) (0.03 mg/kg of body weight) to suppress muscle fasciculations and increased intracranial pressure provoked by succinylcholine. Anaesthesia was induced with a sleeping dose of thiopentone followed by succinycholine (1 to 1.5 mg/kg of body weight). After endotracheal intubation, relaxation was continued by the administration of additional Pavulon in a dose of 5 to 6 mg. Anaesthesia was maintained by ventilation with a gas mixture of 6 0 % N2O and 4 0 % O2. Incremental doses of 1 to 2 mg of chlorpromazine were giVen to maintain the systolic blood pressure blow 103 mm Hg. Induced hypotension was not used, and the systolic pressure never fell below 90 mm Hg during operation in any patient. Two of the patients with a ruptured ACoA aneurysm and 12 of the 18 patients with a ruptured MCA aneurysm received additional treatment with nimodipine. After clipping of the aneurysm, all exposed arterial segments were bathed in a 2.5 X 10~ 5 M solution of nimodipine for at least 10 minutes under direct microscopical visualization. Intravenous administration of 0.5 [ig nimodipine/kg of body weight/min, i.e.,

Tolerance of temporary arterial occlusion in early aneurysm surgery

423

approximately 2 mg/hour* was started at the same time as the topical perivascular application and the infusion was continued for at least 7 days postoperatively by the use of a low dose infusion pump. When the patients had undergone a second, postoperative angiography (control angiogram), the continuous i.v. infusion was changed to oral administration in doses of 45 mg nimodipine X 6 per 24 hours, which medication was maintained for at least another 7 days. Post-operative angiography was performed on all patients on day 10 ± 3 after SAH. The angiographic findings were divided into three groups according to the system of MacPherson and Graham [20]: a) None, or very discrete angiographic vasospasm, i.e., less than V3 reduction in vessel diameter as compared to the appearance on the initial angiogram during the acute stage; b) moderate angiographic vasospasm, i.e., less than 2 h reduction of arterial caliber; and c) severe angiographic vasospasm, i.e., more than 2/3 reduction of arterial caliber. All patients were investigated for neurological deficits occurring immediately after operation or for a delayed onset. All post-operative angiograms were evaluated for signs of thrombembolic complications, any arterial wall changes at the temporary clip location, and cerebral vasospasm. The follow-up period ranged from 2 months to 4 years.

Results ACoA aneurysms Of the 8 patients operated upon for a ruptured ACoA aneurysm, four made a good recovery, two patients were considered to show fair results, one patient did not do well and one patient died. Relevant clinical data, occluded vessel, appearance of immediate or late neurological deficiancies and angiographic findings on control angiography and final clinical condition are given in table 1. An elderly nimodipinetreated patient did not tolerate occlusion of the pericallosal artery for 35 min. and showed immediate new signs of a pericallosal infarction. One patient with bilateral temporary occlusion of the anterior cerebral arteries for 10 minutes showed late deterioration and died. The second nimodipine-treated patient with bilateral temporary occlusion of both anterior cerebral arteries during 11 minutes was classed as having a fair recovery due to impaired CSF outflow requiring an additional shunt procedure; in this case computer tomography (CT) as well as angiography during the acute stage had revealed signs of an early fairly marked ventricular dilatation.

* Auer L.: Personal communication, 1981.

424

P. Ljunggren, H. Säveland and L. Brandt

1

Fig. 1

Patient 10 from table 3. Frontal views before (left) and after (right) (day 12 after SAH) operation on day 3 for a large (20 x 20 mm), broad-based right MCA aneurysm.

Tolerance of temporary arterial occlusion in early aneurysm surgery

Fig. 2

425

Patient 10 from table 3. Side views before (left) and after (right) surgery of right MCA aneurysm.

426

P. Ljunggren, H. Saveland and L. Brandt

MCA aneurysms Relevant clinical and angiographical data in the six first MCA aneurysm patients not given nimodipine are shown in table 2. Four patients tolerated proximal clipping of the MCA immediately after the ICA trifurcation for periods between 4V2 and 13 minutes without developing permanent deficits; none developed deficits of delayed onset. Two patients tolerated distal occlusion of the MCA at the main branching during 18 and 30 minutes, respectively. Table 3 shows relevant clinical and radiological data for the 12 M C A aneurysm patients who also were treated with nimodipine. All patients had a good clinical outcome. The occlusion time varied from 4 to 48 minutes. In cases 2 , 1 1 and 12 (tab. 3) the aneurysm size was 12 X 15 mm, 15 x 15 mm, and of giant size, respectively. In these patients the MCA was temporarily occluded to allow opening of the aneurysm sacs thus permitting adequate positioning of clips over the base of the large, collapsed or partially collapsed aneurysms. Patient 5 also underwent the evacuation of an intracerebral haematoma in the right frontal lobe in the acute stage and in patients 11 and 12 temporal lobe intracerebral haematomas were evacuated as well in the acute stage. Patient 5 showed immediate new focal deficit which, however, were transient and patient 11 showed discrete immediate new deficit which disappeared within 2 4 hours after surgery on day 2 post-SAH. None of the 12 patients developed late cerebral dysfunction. No arterial wall changes at the site of temporary clipping were noticed in postoperative angiograms. However moderate vasospasm was revealed in five patients, and none or insignificant vasospasm in the other seven patients.

Discussion The reduction in cerebral blood flow (CBF) resulting from temporary peri-operative occlusion varied between different patients due to individual variations in the collateral supply and may be highly inhomogeneous within the ischaemic focus [4]. This variability makes it difficult to predict whether a temporary arterial occlusion will contribute to a critical degree of ischaemia. Temporary peri-operative arterial occlusion during early aneurysm surgery theoretically could be hazardous by causing a hypoperfusion syndrome and by increasing the risk of ischaemic complications due to delayed vasospasm. This study indicates however that temporary clipping during the acute stage after SAH leads to neither a clinically detectable hypoperfusion syndrome in terms of immediate new neurological deficiencies after aneurysm operation and temporary clipping nor aggravated late cerebral dysfunction ("clinical vasospasm"), in terms of

427

Tolerance of temporary arterial occlusion in early aneurysm surgery

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