562

Progress Reviews

Cerebral Vasospasm Following AneurysmalSubarachnoid Hemorrhage

N.F. KASSELL, M.D., T. SASAKI, M.D., A.R.T. COLOHAN, M.D., AND G. NAZAR, M.D.

SUMMARY Cerebral vasospasm following aneurysmal subarachnoid hemorrhage is one of the mostimportant causes of cerebral ischemia, and is the leading cause of death and disability after aneurysmrupture. There are two definitions of cerebral vasospasm: angiographic and clinical. Care must be exercisedto be certain that it is clear which entity is being addressed. The diagnosis of the clinical syndrome is one ofexclusion and can rarely be made with absolute certainty. The pathogenesis of cerebral vasospasm is poorlyunderstood. Most current theories focus on the release of factors from the subarachnoid clot. Moreattention must be given to the role of endothelial damage and alterations in the blood-arterial wall barrier.The application of modern techniques for studying vascular smooth muscle which have been developed as aresult of research in the areas of hypertension and atherosclerosis must be applied to the problem of cerebralvasospasm. A stress test to select patients with angiographic arterial narrowing who have adequate cerebralvascular reserve to undergo surgery should be developed. The optimal treatment of vasospasm awaitsdevelopment of agents for blocking or inactivating spasmogenic substances or blocking arterial smoothmuscle contraction. Rheological or hemodynamic manipulations to prevent or reverse ischemic conse-quences of vasospasm are relatively effective, but complicated and hazardous, and should be viewedprincipally as interim measures awaiting development of more specific therapies for the arterial narrowing.

Stroke Vol 16, No 4, 1985

RUPTURED INTRACRANIAL ANEURYSM is amajor public health problem affecting more than28,000 individuals in North America each year.1 2 Inexcess of 19,000 will ultimately die or be disabled. Forperspective, the annual incidence of primary intracra-nial neoplasm is only 10,000 per year.3 Paradoxically,brain tumors are generally perceived as being the morecommon neurological disorder and have received dis-proportionate (although entirely appropriate) attentionand research funding.

In the past, rebleeding — the most dramatic anddreaded complication following aneurysm rupture —was considered the major cause of morbidity and mor-tality. However, recently it has been demonstrated thatthe leading cause of death and disability in patientswith aneurysmal subarachnoid hemorrhage is cerebralvasospasm. Of those patients who reach neurosurgicalreferral centers, vasospasm will kill 7% and maimanother 7%, and 6% will perish and 1% will be ruinedas a result of rebleeding. (Kassell NF, Torner JC, andJane JA: International Cooperative Study on the Tim-ing of Aneurysm Surgery: Preliminary results. Pre-sented at the Annual Meeting of the American Associ-ation of Neurological Surgeons, Atlanta, Georgia,April, 1985)

While vasospasm is of fundamental interest in the

From the Department of Neurological Surgery, University of Virgin-ia, School of Medicine, Charlottesville, Virginia 22908.

Address correspondence to: Neal F. Kassell, M.D., Department ofNeurological Surgery, University of Virginia, School of Medicine,Charlottesville, Virginia 22908.

Received May 29, 1985; accepted May 30. 1985.

management of patients with intracranial aneurysms,there are certain aspects of this disorder which are ofmore general interest and which have for the most partbeen neglected in the field of ischemic stroke. Mostvictims of aneurysmal subarachnoid hemorrhage areyoung (average age 51), otherwise healthy individualswho gradually develop ischemic neurological deficitswhile hospitalized for treatment of their ruptured aneu-rysm (Kassell NF, Torner JC, and Jane JA: Interna-tional Cooperative Study on the Timing of AneurysmSurgery: Preliminary results. Presented at the AnnualMeeting of the American Association of NeurologicalSurgeons, Atlanta, Georgia, April, 1985). If they re-cover, they can return to their premorbid state withmany years of productive life ahead of them. In con-trast, most patients who suffer thromboembolic strokedo so suddenly and then present with fixed neurologi-cal deficits to hospital usually after an interval suffi-cient for infarction to have occurred. These patients aremostly older4 and in whom the thromboembolic strokeis but an indicator of generalized atherosclerosis — aprogressive, fatal, systemic disease from which ap-proximately 45% will die within five years.5 Further-more, since the ischemic deficits from vasospasm oc-cur with a significant delay prior to infarction in ahospital setting under the observation of neurologistsand neurosurgeons, this disorder may be used as animportant model for evaluating diagnostic tests for de-creased cerebral perfusion as well as for studyingtherapeutic interventions for ischemic protection andrescue. To date, full advantage has not been taken ofthese opportunities.

by guest on June 15, 2018http://stroke.ahajournals.org/

Dow

nloaded from

CEREBRAL VASOSPASM/Kassel7 el al 563

DiagnosisThere are two definitions of cerebral vasospasm —

angiographic and clinical — which may not be usedinterchangeably. Angiographic vasospasm is a nar-rowing of the dye column in the major cerebral arterieswhich is usually focal but may be diffuse. The narrow-ing is time-dependent, rarely pronounced before the4th day following the initial hemorrhage and reaches apeak around the 7th day.6-" At that time 40 to 70% ofpatients will have some reduction in the caliber of oneor more of the arteries of the Circle of Willis or itsbranches.6 7-12"14 Due to the variability in the normalanatomy of these vessels and the variability in thedegree and extent in which these arteries are affected,attempts to quantitate vasospasm in a reliable mannerhave been frustrating. At this time the most usefulmeans are those developed by Fisher15 and Weir,10

although the most practical remains the gestalt of anexperienced neuroradiologist or neurosurgeon.

Clinical vasospasm is the syndrome of the ischemicconsequences of cerebral arterial narrowing and ischaracterized by the insidious onset of confusion anddecreased level of consciousness followed by focalmotor and speech impairments and is often heralded byworsening headache and increasing blood pressure.Appearance of the clinical syndrome may be acceler-ated or precipitated by a reduction of blood pressure(usually from antihypertensive therapy), a decrease inintravascular volume, or by surgical manipulations.The time course for clinical vasospasm parallels that ofangiographic vasospasm but while 70% of patientsmay develop arterial narrowing only 20 to 30% willmanifest neurological deficits. l6~19 The discrepancy be-tween the incidence of angiographic and clinical vaso-spasm is probably best explained by differences in thelocation and degree of arterial narrowing and the ade-quacy of collateral circulation.

While the risk of clinical vasospasm is omnipresentin patients who have sustained rupture of an intracrani-al aneurysm, it is often exceedingly difficult to provethat the neurological deficits which occur are related tothe arterial narrowing. The etiology of neurologicaldeterioration in patients with aneurysmal subarachnoidhemorrhage is protean with more than one factor beingoperant in the majority of instances (Kassell NF, Peer-less SJ, Drake CG: Progressive neurological deteriora-tion following subarachnoid hemorrhage. Presented atthe Annual Meeting of the Congress of NeurologicalSurgeons, New Orleans, Louisiana, October, 1976).Currently the diagnosis of vasospasm is primarilybased on the time of onset of the deficits (usually 4—9days following subarachnoid hemorrhage), the rate ofdevelopment of the deficits (hours), the nature of thedeficits (impaired orientation and decreased level ofconsciousness preceding focal deficits) and the exclu-sion of other causes including: rebleeding, intra-cerebral hematoma, or hydrocephalus (by CT scan),metabolic disturbances (hypoxia, hyponatremia), an-giographic or surgical complications, etc. In the past,angiographic confirmation of arterial narrowing wasusually considered mandatory for making the diagno-

sis of clinical vasospasm. Currently, however, theabove criteria are considered to be adequate in mostinstances for the following reasons: 1) even when thearterial narrowing is present other causes are not ex-cluded since, as noted previously, the deficits are fre-quently multifactorial; 2) the inherent risk of angiogra-phy plus the hazard of moving patients from carefullycontrolled environments; and 3) the expense of theprocedure. However, in certain instances angiographyis still warranted, particularly prior to embarking oncomplicated and potentially risky therapy, if the diag-nosis is suspect. A promising alternative to angiogra-phy for demonstrating narrowing of the major cerebralarteries is transcranial pulsed Doppler.20

From the aforementioned comments it is apparentthat it is almost impossible to make the diagnosis ofclinical vasospasm with absolute certainty in manyinstances. This point must be considered carefully indesigning and evaluating clinical trials.

PathogenesisThe pathogenesis of cerebral vasospasm is poorly

understood. Since the original description of angio-graphic vasospasm more than 30 years ago21 consider-able effort has been expended — mostly by neurosur-geons — in investigating the etiology of vasospasm.Studies thus far have failed to yield conclusive evi-dence as to the causative agent(s) or the nature of thearterial narrowing. It remains unclear as to whethervasospasm is a normal or abnormal contraction or fail-ure of relaxation of arterial smooth muscle cells orwhether it represents a cytoarchitectural thickening inthe vessel wall.

The uncertainty regarding the pathogenesis of vaso-spasm is exemplified by the controversy regarding thehistopathological changes in the involved arteries.While it has been reported that the narrowed arteriesare morphologically normal following experimentalsubarachnoid hemorrhage,22 there is little doubt thatmicroscopic alterations do occur in vasospasm.Changes which have been described include: intralu-minal platelet adhesion and aggregation with white celladhesion and thrombus formation,23-24 increased endo-thelial pinocytotic activity or channel formation,25 inti-mal swelling, proliferation, degeneration, and desqua-mation,25"30 opening of interendothelial junctions,25

subendothelial fibroses,31-32 and migration and prolif-eration of smooth muscle cells,33 medial infiltration oflymphocytes, plasma cells and macrophages,26-29-M-35

and deposition of IGG and complement,36 necroses ofsmooth muscle cells,33 corrugation of the internal elas-tic lamina,37 degranulation of perivascular nerve termi-nals and degeneration of perivascular nerves.38"43

No conclusive evidence has yet been forthcoming toindicate whether or not any of these changes are caus-ally related to the arterial narrowing and developmentof neurological deficits or whether they represent epi-phenomenon or a nonspecific reaction to vascular in-jury. Furthermore, it is unclear as to the role of intra-vascular phenomena such as thromboembolism in thegenesis of cerebral ischemia.

by guest on June 15, 2018http://stroke.ahajournals.org/

Dow

nloaded from

564 STROKE VOL 16, No 4, JULY-AUGUST 1985

At this time there is little doubt that blood in thesubarachnoid space is related to the development ofvasospasm and that there is a close association betweenvasospasm and the amount of blood in the subarach-noid space.44"50 Antifibrinolytic therapy which pre-vents dissolution of the clot in the subarachnoid spaceincreases the incidence and perhaps the severity ofclinical vasospasm51"53 and removal of the clot maydecrease the incidence or severity of the ischemic defi-cits.54"56 While bleeding into the subarachnoid spaceappears to be the fundamental initiating event, identifi-cation of specific spasmogenic substances releasedfrom the clot has not been accomplished with certain-ty.57 Putative spasmogens include epinephrine,58"60

norepinephrine,58"63 serotonin,58"6164"68 angioten-sin,59-65 hemoglobin,69"74 thrombin or plasmin,75 fibrindegradation products,7677 prostaglandins,78"83 throm-boxane,84"87 hydroperoxides,88"92 potassium,93"95 andothers.

In addition, it must be noted that subarachnoid hem-orrhage is associated with an abrupt increase in intra-cranial pressure and blood pressure as well as somedegree of cerebral ischemia and hypoxemia.96"99 Thesefactors may also contribute to the development of va-sospasm.

The major contemporary hypotheses regarding thepathogenesis of the arterial narrowing are as follows:

1) Contraction of cerebral arterial smooth musclecells secondary to vasoactive substances inthe CSF,5710°-103 denervation supersensitivi-ty 38-40,42.43 o r a prostacyclin/thromboxane A2

imbalance.104"106

2) Impairment of vasodilatory activity due to:a. prostacyclin/thromboxane A2 imbalance. Ar-

terial wall prostaglandin decreases progres-sively following subarachnoid hemorrhage,probably in association with the progressiveendothelial degeneration.104"106

b. oxyhemoglobin, which is present in bloodyCSF, has been shown to inhibit acetylcho-line-mediated vasodilatation.107 This acetyl-choline-mediated vasodilatation is also inhib-ited by hypoxia,108 and the arterial muscle cellmay be hypoxic as a result of clogging of theadventitial pores with fibrin and red bloodcells.109 Furthermore, the hemoglobin in theCSF may inhibit neurogenic vasodilata-tion,110 as well as endothelial derived relaxingfactor-induced vasodilatation (Fujiwara S,Kassell NF, unpublished data).

3) Proliferative vasculopathy. The mitogenic sub-stances in the platelets — either those in thesubarachnoid clot or those that adhere to the arte-rial lumen as well as a similar substance releasedfrom injured endothelium may cause prolifera-tion of smooth muscle cells and fibroblasts in themedia.1"- "2

4) Vasospasm may be an immunoreactive process.Both an increase in circulating immune com-plexes36 and IgG and C3 deposition in the mediaof the arterial wall of patients with chronic spasm

have been shown."3 It is unclear whether thisimmunoreactivity is responsible for the initiationof an anaphylactoid reaction (and by release ofchemical mediators causing spasm) or a by-prod-uct of an inflammatory process taking place inand around the vessel wall and/or a response tothe formation of antigens (such as smooth mus-cle or endothelial injury or destruction)"4- "5thatmay be occurring during the vasospastic process.

5) Vasospasm may be an inflammatory process.Considerable indirect evidence has been gather-ing that suggest vasospasm may be the result ofan inflammatory process taking place in the arte-rial wall and initiated by the surroundingclot.36- "6""9 Morphological changes compatiblewith an inflammatory process,"8120121 leuko-cytes within the blood vessel wall122 and adherentto the endothelial surface (Nazar G, Kassell NF,unpublished data), the multiple complex originsof vasospasm,123 experimental responses to non-steroidal anti-inflammatory drugs124 and ste-roids,125 and studies on the inflammatory proc-ess126"128 support the concept.

6) The arterial narrowing may be a mechanical phe-nomenon either because the arteries are com-pressed by the periarterial clot or due to distor-tion of the arachnoid bands which tether themajor cerebral arteries in the subarachnoid cis-terns.129

From the above it is apparent that most of the hy-potheses regarding the development of the arterial nar-rowing assume that the etiology is related to substancesliberated from the subarachnoid clot resulting in con-traction or morphological changes in the vessel wall.However, it has recently been hypothesized that theendothelial damage resulting from the subarachnoidhemorrhage may be related to the subsequent arterialnarrowing.130 The cause of the endothelial injury hasnot been established but arterial hypertension, in-creased intracranial pressure and, in particular, sub-arachnoid blood all increase transendothelial perme-ability acutely, by increasing vesicular transport orchannel formation (Sasaki T, Kassell NF, unpublisheddata). Instillation of synthetic TXA2 into the CSF pro-duces similar effects (Zuccarello M, Kassell NF, un-published data).

Clinically, it has been observed that contrast en-hancement in the basal cisterns in the region of themajor cerebral arteries indicating increased arterialpermeability occurs in certain patients following aneu-rysm rupture and that these patients are most prone todevelop vasospasm.131"134 In the subacute and chronicstages of subarachnoid hemorrhage, arterial endotheli-al cells degenerate and there is opening of the interen-dothelial tight junctions, resulting in marked distur-bance in the blood arterial wall barrier.130 Thisbreakdown of the blood arterial wall barrier may allowaccess of constrictor substances in plasma (such ascatecholamines or prostaglandins) to the smooth mus-cle cells. Furthermore, platelets may adhere to eitherdamaged endothelium or denuded subendothelium and

by guest on June 15, 2018http://stroke.ahajournals.org/

Dow

nloaded from

CEREBRAL VASOSPASM/Kasseil et al 565

release additional constrictor substances such as sero-tonin.'"• l36 The effect of the vasoactive substances inplasma may be particularly pronounced since thesmooth muscle cells closest to the lumen are the mostsensitive to constrictor agonists.137 In addition, sub-arachnoid hemorrhage has been shown to result in de-polarization of arterial smooth muscle cells, makingthem more prone to contraction.138 Damage of endo-thelium may result in loss of the potent vasodilator,prostacyclin,10M03 while allowing the unopposed ac-tion of thromboxane A2 released from platelets. Addi-tional vasoactive substances may be released fromthese adhering platelets as well as white bloodcells 126-127'l35'136

Medial thickening and luminal narrowing may beproduced by proliferation of smooth muscle cells andfibroblasts, either caused by platelet derived growthfactor released from platelets in the subarachnoid clotor from platelets adhering to the arterial luminal sur-face of the arterial wall or to a similar substancereleased from damaged endothelium,137139 or thespasmogenic effects of thrombin, plasmin, andfibrinogen.140

From the previous discussion it may be surmisedthat the pathogenesis of cerebral vasospasm is mostlikely a complicated, multifactorial process. Investiga-tions in the past have been hampered by lack of asatisfactory animal model of vasospasm.'41"143 Manystudies have been conducted in the acute stage follow-ing applications of blood or other substances to arteriesin vivo or in vitro. These studies may be appropriatefor understanding short-lived arterial contraction butare not optimal for unraveling the complexities of thedelayed, prolonged arterial narrowing resulting fromsubarachnoid hemorrhage.

The problems with most models of subarachnoidhemorrhage were that: 1) it was difficult to create re-producible arterial narrowing, probably because mostanimals have a more simple, less trabeculated sub-arachnoid space and perhaps a more active fibrinolyticsystem in the CSF than humans and 2) almost all ani-mals failed to develop delayed progressive neurologi-cal deficits.144

Recently, reasonably good models of angiographicvasospasm have been developed using application ofblood around major cerebral arteries under direct vi-sion145- l46 or double injections of blood into the basalcisterns.25-i09- i47~149 The difficulty in producing neuro-logical deficits is probably related to the relative resis-tance of lower species to cerebral ischemia perhapsbecause of more effective collateral pathways as wellas less eloquent brains. This is not a major limitation instudies of the pathogenesis of arterial narrowing sincemorphological and angiographic endpoints are ade-quate for most investigations, but may be of greaterconcern in studies of treatment of clinical vasospasmwhere the most relevant endpoint is reversal of ischem-ic neurological deficits. Another problem with animalmodels is the rather marked species differences in reg-ulation of the cerebral circulation.6386' 15°-151

In the past decade, there have been profound ad-

vances in vascular smooth muscle morphology, physi-ology, and pathology stimulated as a result of the in-tense interest in atherosclerosis and hypertension.Most developments have related to the systemic circu-lation, rather than the cerebral circulation. In the not-too-distant future, substantial advances in the under-standing of the pathogenesis of cerebral vasospasmmay be anticipated as state-of-the-art techniques areapplied to the problem. These include sophisticatedmorphological techniques, tissue culture of smoothmuscle and endothelium, and in vivo and in vitromethods for studying biochemistry and pharmacologyof cerebral arteries.

Parenthetically, the appropriateness of the term va-sospasm may be questioned since the pathogenesis ofvasospasm is unclear, and the arterial narrowing maynot at all be related to a spastic phenomenon of smoothmuscle cells. For example, the delayed, prolonged,irreversible arterial narrowing which occurs after sub-arachnoid hemorrhage appears to be much differentfrom the vasospasm observed in the coronary circula-tion of patients with Prinzmetal's angina. Nonetheless,the term cerebral vasospasm is well defined and in-grained in the literature. Accordingly, its use should becontinued with the only qualification that it must al-ways be clear as to whether reference is being made tothe clinical or angiographic variety.

PathophysiologyCompared to the pathogenesis of cerebral vaso-

spasm the pathophysiology of this disorder appearsmore straightforward and is better understood.

The arterial narrowing which occurs following sub-arachnoid hemorrhage results in increased cerebralvascular resistance. How far down the arterial tree thisnarrowing extends remains problematical, since theonly vessels visualized by angiography are the Circleof Willis and its primary and secondary branches.Whether pial and penetrating arteries and arterioles arenarrowed has not been established. It is likely, how-ever, that the process does extend to arteriolar level,since red blood cells and presumably plasma contain-ing spasmogens extend well into the Virchow-Robinspaces following subarachnoid hemorrhage.152 Thisnotwithstanding, the angiographically demonstratedvasospasm is probably sufficient to reduce cerebralblood flow to ischemic levels, since approximatelyhalf of the cerebral vascular resistance is located inthese conducting vessels.l53 Initially, in the presence ofarterial narrowing autoregulation maintains cerebralblood flow constant, but if the narrowing progresses,the limits of autoregulation may be exceeded and cere-bral blood flow falls. Since the brain is supplied withroughly twice the amount of blood flow required fornormal function, no neurological impairments mayinitially result. However, as blood flow decreasesbelow the ischemic threshold, neurological signs andsymptoms may become overt and, if narrowing pro-gresses and the flow decreases further, infarction mayoccur.

In ischemic situations caused by vasospasm, the

by guest on June 15, 2018http://stroke.ahajournals.org/

Dow

nloaded from

566 STROKE VOL 16, No 4, JULY-AUGUST 1985

major cerebral arteries are narrowed and blood flow isreduced but cerebral blood volume is paradoxicallyincreased. This may be due to dilatation of more distalresistance vessels and collateral channels as well ascollection of blood in the capacitance vessels of theischemic zones.154

As noted previously, patients may evidence a sig-nificant degree of angiographic arterial narrowing yethave adequate cerebral blood flow to be essentiallynormal clinically or because of the excess cerebralblood flow because perfusion is preserved through au-toregulation. Whether or not these patients are candi-dates for surgery is controversial. While these patientsmay be normal preoperatively, their cerebral circula-tory reserve may be exhausted so that the surgical oranesthetic manipulations such as brain retraction, sys-temic arterial hypotension, temporary arterial occlu-sion, etc. may decrease flow and cause infarctionwhich becomes evident upon awakening from the op-erative procedure. The timing of surgery for such pa-tients is still controversial, but most surgeons will waituntil vasospasm resolves before proceeding with oper-ation.155 In these circumstances, dynamic tests of thereserve capacity of the cerebral circulation may beuseful in determining which patients can tolerate sur-gery. Such tests could involve stressing the cerebralcirculation by lowering arterial pressure or increasingarterial pCO2 while measuring the cerebral blood flow,the brain's electrical activity, and the neurological ex-amination.156

A possible factor contributing to the developmentof ischemic deficits may be intra-arterial thromboem-bolism, particularly involving the smaller arter-ies.23- 26-l57 l58 If intravascular thromboembolismproves to be a component of the syndrome of vaso-spasm, new avenues of therapy, namely, anticoagula-tion or antiplatelet agents, may prove beneficial.157-159

TreatmentThe treatment of cerebral vasospasm may be consid-

ered in the following categories: 1) prevention or re-versal of the arterial narrowing; 2) prevention or rever-sal of the ischemic neurological deficits; and 3)protection from infarction.

Efforts to prevent vasospasm from developing andto reverse it once it has occurred have been hamperedby lack of understanding of the etiology of the arterialnarrowing and, to date, no measures have proven suc-cessful.160 A theoretically attractive approach for pre-venting or ameliorating the arterial narrowing is re-moval of clot from the basal cisterns in the daysimmediately following the hemorrhage, prior to theonset of vasospasm. The clot can be removed mechani-cally with suction and irrigation at the time of cranioto-

my, or perhaps more attractively, by instillationof fibrinolytic substances such as streptokinase, uro-kinase or plasmin into the cerebrospinal fluid.164 Asurprisingly large amount of subarachnoid clot canindeed be removed through a unilateral craniotomyand some surgeons have even resorted to bilateral cra-niotomies in an attempt to remove as much of the clot

as possible.165 Mechanical removal of the clot can onlybe accomplished with some bruising of pial banks ordamage to small vessels.166 167 While there are a num-ber of optimistic reports that this measure is effective,other reports indicate that the incidence or severity ofvasospasm is not significantly decreased.168 Lysis ofthe subarachnoid hematoma pharmacologically ismuch more attractive in theory, since it should beaccomplished more completely and with less damage,but, although clinical studies have been started,169-17°there is currently little information regarding the effec-tiveness of this approach. However, subarachnoid fi-brinolytic therapy is definitely an area which warrantsfurther investigation.

A large number of agents have been used to preventor reverse the arterial narrowing; an exhaustive reviewof this topic was published by Wilkins in 1980.160 Pres-ently, no means have been definitely identified fortreating cerebral vasospasm. The drugs which havereceived the most contemporary interest are the cal-cium channel blocking agents,171"177 based on the as-sumption that contraction of cerebral arterial smoothmuscle cells is a calcium-dependent phenomenonwhich can be inhibited by preventing influx of extra-cellular calcium. However, the contraction of cerebralarterial smooth muscle cells to a variety of agonists,particularly those found in the CSF following sub-arachnoid hemorrhage, has been shown to rely in largepart upon intracellular calcium.178 This may accountfor the observation that these calcium channel blockingagents do not appear to prevent or reverse narrowing ofthe major arteries, although there is a reasonable sug-gestion that calcium channel blocking agents may pre-vent or reverse ischemic neurological deficits.179 Per-haps the most attractive approach to preventing orreversing arterial narrowing is to prevent or reverseactivation of the actin-myosin complex by calmodulin,the final step in all processes leading to arterial smoothmuscle contraction. Initial studies with calmodulinblocking agents have been encouraging.180"184

Other drugs which have recently been evaluated forthe treatment of vasospasm include the angiotensinconverting enzyme inhibitor teprotide,185-186 throm-boxane A2 synthetase inhibitors,187"189 prostacy-clin,190191 steroids,149192 nonsteroidal anti-inflamma-tory agents,124125 and free radical scavenging agentssuch as Vitamin E.193-194 The efficacy of all of theabove must be considered controversial at best; there iscurrently little to suggest that any is effective in thetreatment of the arterial narrowing that is such an enor-mous clinical problem.

Effective efforts for preventing and reversing angio-graphic vasospasm await definition of the pathogene-sis of the process. The nature of the arterial narrowingmust be worked out and agents found for blocking orinactivating the spasmogenic substance or preventingthe contraction of arterial smooth muscle cells. Specif-ic agents for blocking or inactivating the spasmogenicsubstances should be more effective than nonspecificagents for preventing arterial smooth muscle cell con-traction since the latter would affect not only the in-

by guest on June 15, 2018http://stroke.ahajournals.org/

Dow

nloaded from

CEREBRAL VASOSPASM/Kasw// et al 567

volved cerebral vessels, but the normal vessels in thebrain and perhaps other organs.

The prevention or reversal of ischemic deficits fromvasospasm can be considered in three categories: mea-sures to improve blood flow by altering the rheologicalcharacteristics of the blood; measures to improve oxy-gen delivered to the tissues; and hemodynamic mea-sures to increase cerebral blood flow. These ap-proaches are generally complicated, hazardous, andnon-physiological and should be considered primarilyinterim solutions until measures for specifically pre-venting or reversing the arterial narrowing can be de-veloped.

Drugs for improving the rheological characteristicsof the blood include the use of calcium channel block-ing agents,195 prostacyclin,196 heparin,160 hemodilu-tion,197-'" dextran,200"202 mannitol,203 and albumin.204

Calcium channel blocking agents exert their effectprimarily by dilating the leptomeningeal collateralarteries205 but may also work by improving red bloodcell deformability and by exerting an antiplatelet ag-gregating effect.195 Heparin and prostacyclin may pre-vent intravascular thromboembolism206 and the lattermay also be effective in dilating leptomeningeal collat-erals.207 Mannitol has the effect of improving red bloodcell deformability208 and it also is a free radical scav-enging agent.193 Hemodilution may decrease viscosityand thereby improve cerebral blood flow.209 However,the optimum hematocrit in ischemic situations has notbeen established and there may be a considerabletrade-off between decreased viscosity, increased bloodflow and oxygen delivery.209

There are two approaches for improving oxygendelivery to brain tissue made ischemic by vasospasm.The first is the use of hyperbaric oxygen210 and thesecond is the use of fluorinated hydrocarbons such asfluosol.2"-212 The two approaches may be combinedadvantageously.

Improving the hemodynamic status of patients withneurological deficits from vasospasm in an attempt toimprove cerebral blood flow has proven to be a reason-ably effective, although complicated, approach. Car-diac output may be increased by increasing intravascu-lar volume and by the use of chronatropic and inotropicagents such as isoproterenol. Increasing intravascularblood volume without increasing cardiac output ormean arterial pressure may improve cerebral bloodflow by increasing pulse pressure.213 This is a relative-ly new concept developed by Kindt and associates andit appears to be of considerable importance. The finalapproach is to increase cerebral perfusion pressure,defined as the difference between systemic arterial andintracranial pressures, either by reducing intracranialpressure or by increasing systemic arterial pressure.The theory behind this is that the blood flow in theischemic zones is pressure passive since the vessels aremaximally dilated and autoregulation is abolished andtherefore arterial hypertension is induced with va-sopressor agents. In practice, at least 70% of neuro-logical deficits from vasospasm can be reversed usinga combination of increased cardiac output and in-

creased arterial pressure if treatment is initiated prior toinfarction.214 Hypertensive/hypervolemic therapy iscomplicated and hazardous and requires invasive mon-itoring and intensive care.

In those instances where the ischemic deficits can-not be prevented or reversed, there are several treat-ments which may be employed in an attempt to providea degree of protection. Steroids may stabilize lysoso-mal and cell membranes.215 Calcium channel blockingagents may be beneficial in these circumstances bypreventing the passage of lethal amounts of extracellu-lar calcium into the cell.216 High dose barbiturate ther-apy has been employed as a last ditch effort in a num-ber of cases in an attempt to decrease the metabolicactivity of the brain to a level which can be supportedby the compromised delivery of substrate. Barbituratecoma is a heroic measure and the results have beendiscouraging to date.217

References1. Kassell NF, Drake CG: Timing of aneurysm surgery. Neurosur-

gery 10: 514-519, 19822. Kassell NF, Drake CG: Review of the management of saccular

aneurysms. Neurological Clinics of North America 1: 73-86,1983

3. Walker MD, Chap XXI-1 Brain and peripheral nervous systemtumors in Holland and Frei (eds) Cancer Medicine. Phila: Lee &Ferberger, 1982, p 1603

4. Matsumoto N, Whisnant JP, Kurland LT, Okazaki H: Naturalhistory of stroke in Rochester, Minnesota, 1955 through 1969: Anextension of a previous study, 1945 through 1954. Stroke 4:20-29, 1972

5. Sacco RL, Wolf PA, Kannel WB, McNamara PM: Survival andrecurrence following stroke — The Framingham study. Stroke 13:290-295, 1982

6. Graf CJ, Nibbelink DW: Cooperative study of intracranial aneu-rysms and subarachnoid hemorrhage. Stroke 5: 559-610, 1974

7. Saito I, Sano K: Vasospasm after aneurysm rupture: Incidence,onset, and course. In Wilkins RH (ed): Cerebral Arterial Spasm.Baltimore, Williams & Wilkins, 1980, pp 294-301

8. Bergvall U, Galera R: Time relationship between subarachnoidhemorrhage, arterial spasm, changes in cerebral circulation andposthemorrhagic hydrocephalus. Acta Radiol (Diagn) 9: 229-237, 1969

9. Kwak R, Niizuma H, Ohi T, Suzuki J: Angiographic study ofcerebral vasospasm following rupture of intracranial aneurysms:Part 1. Time of appearance. Surg Neurol 11: 257-262, 1979

10. Weir B, Grace M, Hansen J, Rothberg C: Time course of vaso-spasm in man. J Neurosurg 48: 173-178, 1978

11. Kagstrom E, Greitz T, Hanson J, Galera R: Changes in cerebralblood flow after subarachnoid hemorrhage. In deVet AC (ed):Proceedings of the Third International Congress of NeurologicalSurgery, Amsterdam, Excerpta Medica Foundation, 1965, pp629-633

12. Allcock JM, Drake CG: Ruptured I-C Aneurysms: the role ofarterial spasm. J Neurosurg 22: 21-29, 1965

13. Odom GL: Cerebral vasospasm. Clin Neurosurg 22: 29-58, 197514. Fletcher TM, Taveras JM, Pool JL: Cerebral vasospasm in angi-

ography for intracranial aneurysms: Incidence and significance inone hundred consecutive angiograms. Arch Neurol 1: 38—47,1959

15. Fisher CM, Robertson GH, Ojemann RG: Cerebral vasospasmwith ruptured saccular aneurysm. The clinical manifestations.Neurosurgery 1: 245-248, 1977

16. Sundt TM Jr, Whisnant JP: Subarachnoid hemorrhage from intra-cranial aneurysms. Surgical management and natural history ofdisease. N Engl J Med 299: 116-122, 1978

17. Post KD, Flamm ES, Goodgold A, Ransohoff J: Ruptured intra-cranial aneurysms. Case morbidity and mortality. J Neurosurg 46:290-295, 1977

by guest on June 15, 2018http://stroke.ahajournals.org/

Dow

nloaded from

568 STROKE V O L 16, No 4, JULY-AUGUST 1985

18. Nibbelink DW, Torner JC, Henderson WG: Intracranial aneu-rysms and subarachnoid hemorrhage. A cooperative study. Anti-fibrinolytic therapy in recent onset subarachnoid hemorrhage.Stroke 6: 622-629, 1975

19. Kodama N, Mizoi K, Sakurai Y, Suzuki J: Incidence and onset ofvasospasm. In Wilkins RH (ed): Cerebral Arterial Spasm. Balti-more, Williams & Wilkins, 1980, pp 361-365

20. Harders A, Gilsbach J: Transcranial Doppler sonography. Ultra-scharh Med 5(5): 237-245, 1984

21. Ecker A, Riemenschneider PA: Arteriographic demonstration ofspasm of the intracranial arteries with special reference to sacculararterial aneurysms. J Neurosurg 8: 660-667, 1951

22. Weir B, Erasmo R, Miller J, Mclntyre J, Secord S, Milke B:Vasospasm in response to repeated subarachnoid hemorrhage inthe monkey. J Neurosurg 33: 395-406, 1970

23. Grady PA, Blaumanis OR, Nelson ER: Morphology and flowdynamics of focal arterial constriction. In Wilkins RH (ed): Cere-bral Arterial Spasm. Baltimore, Williams & Wilkins, 1980, pp107-112

24. Nelson E, Geitz SD, Rennels ML, Forbes MS, Kawamura J:Scanning transmission electron microscopic studies of arterialendothelium following experimental vascular occlusion. In Cer-vos-Navarro J, Betz E, Mistokos F, Willenweber R (eds) TheCerebral Vessel Wall. New York: Raven Press, 1976, pp 33-39

25. Sasaki T, Kassell NF, Yamashita M, Fujiwara S: Disturbances ofblood-brain barrier and cerebral arterial permeability followingexperimental subarachnoid hemorrhage. Xllth Annual Meeting ofthe Society of Neurosurgical Anesthesia and Neurologic Support-ive Care, pp 20-22, 1984

26. Fein JM, Flor WJ, Cohan SL, Parkhurst J: Sequential changes ofvascular ultrastructure in experimental cerebral vasospasm.Myonecrosis of subarachnoid arteries. J Neurosurg 41: 49-58,1974

27. Alksne JF, Smith RW: Experimental models of spasm. ClinNeurosurg 24: 216-227, 1977

28. Simeone FA, Ryan KG, Cotter JR: Prolonged experimental cere-bral vasospasm. J Neurosurg 29: 357-366, 1968

29. Tanabe Y, Sakata K, Yamada H, Ito T, Takada M: Cerebralvasospasm and ultrastructural changes in cerebral arterial wall. JNeurosurg 49: 229-238, 1978

30. Joris I, Majno G: Endothelial changes induced by arterial spasm.Am J Pathol 102: 346-358, 1981

31. Mizukami M, Kin H, Araki G, Mihara H, Yoshida Y: Is angio-graphic spasm real spasm? Acta Neurochir (Wien) 34: 247-259,1976

32. Smith RR, Clower BR, Peeler DF Jr, Yoshioka J: The angiopathyof subarachnoid hemorrhage: Angiographic and morphologic cor-relates. Stroke 14: 240-245, 1983

33. Clower BR. Haining JL, Smith RR: Pathophysiological changesin the cerebral artery after subarachnoid hemorrhage. In WilkinsRH (ed): Cerebral Arterial Spasm. Baltimore, Williams & Wil-kins, 1980, pp 124-131

34. Hughes JT, Schianchi PM: Cerebral artery spasm. A histologicalstudy at necropsy of the blood vessels in cases of subarachnoidhemorrhage. J Neurosurg 48: 515-525, 1978

35. Tani E, Yamagata S, Ito Y: Intercellular granules and vesicles inprolonged cerebral vasospasm. J Neurosurg 48: 179-189, 1978

36. Hoshi T, Shimizu T, Kito K, Yamasaki N, Takahaski K, Taka-hashi M, OkadaT, Kasuya H, Kitamura K: Immunological studyof late cerebral vasospasm in subarachnoid hemorrhage. Detec-tion of immunoglobulins, C3, and fibrinogen in cerebral arterialwalls by immunofluorescence method. Neurol Med Chir (Tokyo)24: 647-654, 1984

37. Mayberg MR, Hauser OW, Sundt TM Jr: Ultrastructural changesin feline arterial endothelium following subarachnoid hemor-rhage. J Neurosurg 48: 49-57, 1978

38. Peerless SJ, Kendall MJ: Cerebral vasospasm. Experimental cere-bral vasospasm. In Whisnant JP, Sandok BA (eds): Proceedingsof the Ninth Princeton Conference on Cerebral Vascular Disease.New York, Grune & Stratton, 1975, pp 49-58

39. Fraser RAR, Stein MM, Barrett RE. Pool JL: Noradrenergicmediation of experimental cerebrovascular spasm. Stroke 1:356-362, 1970

40. Owman C, Edvinsson L, Sahlin C, Svendgaard NA: Transmitterchanges in perivascular sympathetic nerves after experimental

subarachnoid hemorrhage. In Wilkins RH (ed): Cerebral ArterialSpasm. Baltimore, Williams & Wilkins, 1980. pp 279-283

41. Yoshioka J, Clower BR, Smith RR: The angiopathy of subarach-noid hemorrhage. I. Role of vessel wall catecholamines. Stroke15: 288-294, 1984

42. Lobato RD, Marin J, Salaices M, Burgos J, Rivilla F, Garcia AG:Effect of experimental subarachnoid hemorrhage on the adrener-gic innervation of cerebral arteries. J Neurosurg 53: 477-479,1980

43. Lobato RD, Marin J, Salaices M, Rivilla F, Burgos J: Cerebrovas-cular reactivity to noradrenaline and serotonin following experi-mental subarachnoid hemorrhage. J Neurosurg 53: 480-485,1980

44. Fisher CM, Kistler JP, David JM: Relation of cerebral vasospasmto subarachnoid hemorrhage visualized by computerized tomo-graphic scanning. Neurosurgery 6: 1-9, 1980

45. Mizukami M.TakemaeT, Kin H, KawaseT, Araki G: Computedtomography of ruptured intracranial aneurysm in acute stage —relationship between vasospasm and high density on CT scan.Brain and Nerve (Tokyo) 30: 861-866, 1978

46. Mizukami M, Takemae T, Tazawa T, Kawase T, Matsuzaki T:Value of computed tomography in the prediction of cerebral vaso-spasm after aneurysmal rupture. Neurosurgery 7: 583-586. 1980

47. Symon L, Bell BA, Kendall B: Relationship between effusedblood and clinical course and prognosis in aneurysmal subarach-noid hemorrhage: A preliminary computerized tomography scanstudy. In Wilkins RH (ed): Cerebral Arterial Spasm. Baltimore,Williams & Wilkins, 1980, pp 409-411

48. Saito I, Sano K: Vasospasm following rupture of cerebral aneu-rysms. Neurol Med Chir (Tokyo) 19: 103-107. 1979

49. Suzuki J, Komatsu S, Sato T, Sakurai Y: Correlation between CTfindings and subsequent development of cerebral infarction due tovasospasm in subarachnoid hemorrhage. Acta Neurochir (Wien)55: 63-70, 1980

50. Kistler JP, Crowell RM, Davis KR, Heros R. Ojemann RG,Zervas T, Fisher CM: The relation of cerebral vasospasm to theextent and reaction of subarachnoid blood visualized by CT scan:A prospective study. Neurology (NY) 33(4): 424-436, 1983

51. Kagstrom E, Palma L: Influence of antifibrinolytic treatment onthe morbidity in patients with subarachnoid hemorrhage. ActaNeurol Scand 48: 257, 1972

52. Schisano G: The use of antifribinolytic drugs in aneurysmal sub-arachnoid hemorrhage. Surg Neurol 10: 217-222, 1978

53. Kassell NF, Torner JC, Adams HP: Antifibrinolytic therapy in theacute period following aneurysmal subarachnoid hemorrhage. JNeurosurg 61: 225-230, 1984

54. Saito I, Ueda Y, Sano K: Significance of vasospasm in the treat-ment of ruptured intracranial aneurysms. J Neurosurg 47:412-429, 1977

55. Sano K, Saito I: Timing and indication of surgery for rupturedintracranial aneurysms with regard to cerebral vasospasm. ActaNeurochir (Wien) 41: 49-60. 1978

56. Suzuki J. Yoshimoto T, Onuma T: Early operations for rupturedintracranial aneurysms — Study of 31 cases operated on withinfirst four days after ruptured aneurysm. Neurol Med Chir (Tokyo)18: 83-89, 1978

57. Sasaki T, Asano T, Takakura K, Sano K, Kassell NF: Nature ofthe vasoactive substance in CSF from patients with subarachnoidhemorrhage. J Neurosurg 60: 1186-1191, 1984

58. Nielsen KC. Owman C: Contractile response and amine receptormechanisms in isolated middle cerebral artery of the cat. BrainRes 27: 33-42, 1971

59. Allen GS, Henderson LM, Chou SN, French LA: Cerebral arterialspasm. Part 1: In vitro contraction of vasoactive agents on caninebasilar and middle cerebral arteries. J Neurosurg 40: 433-441,1974

60. Allen GS, Gross CJ: Cerebral arterial spasm. Part 7: In vitroeffects of alpha adrenergic agents on canine arteries from sixanatomical sites and six blocking agents on serotonin-inducedcontractions of the canine basilar artery. Surg Neurol 6: 63-70,1976

61. Zervas NT, Lavyne MH. Negoro M: Neurotransmitters and thenormal and ischemic cerebral circulation. N Engl J Med 293:812-816, 1975

62. Toda N: Influence of dopamine and norepinephrine on isolated

by guest on June 15, 2018http://stroke.ahajournals.org/

Dow

nloaded from

CEREBRAL VASOSPASM//Cfl.v.se// et al 569

cerebral arteries of the dog. Br J Pharmacol 58: 121-126, 197663. Toda N: Alpha adrenergic receptor subtype in human, monkey

and dog cerebral arteries. J Pharmacol Exp Ther 226: 861-868,1983

64. Raynor RB. McMurtry JG, Pool JL: Cerebrovascular effects oftopically applied serotonin in the cat. Neurology (Minneap) 11:190-195, 1961

65. Kapp J, Mahaley MS, Odom GL: Cerebral arterial spasm. Part 2:Experimental evaluation of mechanical and humoral factors inpathogenesis. J Neurosurg 29: 339-349, 1968

66. White RP, Heaton JA, Denton IC: Pharmacological comparisonof prostaglandin F2a, serotonin and norepinephrine on cerebro-vascular tone of monkey. Eur J Pharmacol 15: 300-309, 1971

67. Allen GS, Gold LHA, Chou SN, French LA: Cerebral arterialspasm. Part 3: In vivo intracisternal production of spasm by sero-tonin and blood and its reversal by phenoxybenzamine. J Neuro-surg 40: 451-458, 1974

68. White RP, Hagen AA, Morgan H, Dawson WN, Robertson JT:Experimental study on the genesis of cerebral vasospasm. Stroke6: 52-57, 1975

69. Miyaoka M, Nonaka T, Watanabe H, Chigasaki H, Ishii S: Etiol-ogy and treatment of prolonged vasospasm: Experimental andclinical studies. Neurol Med Chir (Tokyo) 16: 103-114, 1976

70. Osaka K: Prolonged vasospasm produced by the breakdown prod-ucts of erythrocytes. J Neurosurgery 47: 403-411, 1977

71. Sonobe M, Suzuki J: Vasospasmogenic substance produced fol-lowing subarachnoid haemorrhage, and its fate. Acta Neurochir(Wien) 44: 97-106, 1978

72. Ozaki N, Mullan S: Possible role of the erythrocyte in causingprolonged cerebral vasospasm. J Neurosurg 51: 773-778, 1979

73. Tanishima T: Cerebral vasospasm: contractile activity of hemo-globin in isolated canine basilar arteries. J Neurosurg 53:787-793, 1980

74. Wellum GR, Irvine TW, Zervas NT: Cerebral vasoactivity ofheme proteins in vitro: some mechanistic considerations. J Neuro-surg 56: 777-783, 1982

75. White RP, Chapleau CE, Dugdale M, Robertson JT: Cerebralarterial contractions induced by human and bovine thrombin.Stroke 11: 363-368, 1980

76. Ito M: Experimental vasospasms — significance of oxyhemoglo-bin, fibrin degradation products and breakdown products of whiteghost in the pathogenesis of cerebral vasospasms. Treatment ofvasospasms with gabexate mesilate and diphenhydramine. NeurolMed Chir (Tokyo) 20: 225-236, 1980

77. ForsterC, Mohan J, Whalley ET: Interaction of fibrin degradationproducts and 5-hydroxytryptamine on various vascular smoothmuscle preparations: possible role in cerebral vasospasm. In Wil-kins RH (ed): Cerebral Arterial Spasm. Baltimore, Williams &Wilkins, 1980, pp 186-189

78. Handa J, Yoneda S, Matsuda M, Handa H: Effects of prostaglan-dins A, E|, E2, and F2a on the basilar artery of cats. Surg Neurol2: 251-255, 1974

79. Kapp JP, Robertson JR, White RP: Spasmogenic qualities ofprostaglandin F2a in the cat. J Neurosurg 44: 173-175, 1976

80. Morgan H, White RP, Pennink M, Robertson JT: Prostaglandinsand experimental cerebral vasospasm. Surg Forum 23: 447-448,1972

81. Yamamoto YL, Feindel W, Wolfe LS, Katoh H, Hodge CP:Experimental vasoconstriction of cerebral arteries by prostaglan-dins. J Neurosurg 37: 385-397, 1972

82. Rosenblum WI: Effects of prostaglandins on cerebral blood ves-sels: Interaction with vasoactive amines. Neurology (Minneap)25: 1169-1171, 1975

83. Asano T, Sasaki T, Ochiai C, Takakura K: In vitro evaluation ofthe inhibitory action of PGI2 to vasoconstrictions induced byvarious prostaglandins, serotonin and hemoglobin using the ca-nine basilar artery. Neurol Med Chir (Tokyo) 22: 507-512, 1982

84. Ellis EF, Nies AS, Oates JA: Cerebral arterial smooth musclecontraction by thromboxane A2. Stroke 8: 480-482, 1977

85. Toda N: Mechanism of action of carbocyclic thromboxane A2 andits interaction with prostaglandin I-, and verapamil in isolatedarteries. Cir Res 51: 675-682, 1982

86. Sasaki T, Kassell NF, Tomer JC, Maixner W, Turner D: Pharma-cological comparison of isolated monkey and dog cerebral arter-ies. Stroke, 1985 (in press)

87. Von Hoist H, Granstrom E. Hammarstrom S, Samuelsson B,Steiner L: Effect of leucotriene C4, D4, prostacyclin and throm-boxane A2 on isolated human cerebral arteries. Acta Neurochir(Wien) 62": 177-185. 1982

88. Sasaki T, Wakai S, Asano T, Watanabe T, Kirino T. Sano K: Theeffect of a lipid hydroperoxide of arachidonic acid on the caninebasilar artery. An experimental study on cerebral vasospasm. JNeurosurg 54: 357-365, 1981

89. Sasaki T, Asano T, Sano K: Cerebrl vasospasm and free radicalreactions. Neurol Med Chir (Tokyo) 20: 145-153. 1980

90. Koide T, Noda Y, Hata S, Sugioka K, Kobayashi S, Nakano M:Contraction of the canine basilar artery following lineoleic, ara-chidonic. 13-hydroperoxylineoleic, or 15-hydroperoxyarachi-donic acid (41294). Proc Soc Exp Biol Med 168: 399-402, 1981

91. Asano T, Tanishima T, Sasaki T, Sano K: Possible participationof free radical reactions initiated by clot lysis in the pathogenesisof vasospasm after subarachnoid hemorrhage. In Wilkins RH(ed): Cerebral Arterial Spasm. Baltimore, Williams & Wilkins,1980, pp 190-201

92. Sano K: Cerebral vasospasm and aneurysm surgery. Clin Neuro-surg 30: 13-58. 1983

93. TodaN: Responsiveness to potassium and calcium ions of isolatedcerebral arteries. Am J Physiol 227: 1206-1-211, 1974

94. Wilkins RH. Levitt P: Potassium and the pathogenesis of cerebralarterial spasm in dog and man. J Neurosurg 35: 45-50, 1971

95. Shiguma M: Change in the ionic environment of cerebral arteriesafter subarachnoid hemorrhage. Especially of potassium ion con-centration in subarachnoid hematoma and its role in cerebral vaso-spasm. Neurol Med Chir (Tokyo) 22: 805-812, 1982

96. Farrar JK Jr: Chronic cerebral arterial spasm: The role of intra-cranial pressure. J Neurosurg 43: 408-417, 1975

97. Johnston IH, Rowan JO. Haper AM, Jennett WB: Raised intra-cranial pressure and cerebral blood flow. J Neurol NeurosurgPsychiatry 35: 285-296, 1972

98. Farrar JK Jr, Roach MR: The effects of increased intracranialpressure on flow through major cerebral arteries in vitro. Stroke 4:795-806, 1973

99. Beks JWF: Cerebral vasospasm and increased intracranial pres-sure. In Wilkins RH (ed). Cerebral Arterial Spasm, Baltimore,William & Wilkins, 1980, pp 412-413

100. Allen GS, Gross CJ, French LA, Chou SN: Cerebral arterialspasm. Part 5: In vitro contractile activity of vasoactive agentsincluding human cerebrospinal fluid on human basilar and anteri-or cerebral arteries. J Neurosurg 44: 594-600, 1976

101. Boullin DJ, Mohan J, Grahame-Smith DG: Evidence for the pres-ence of a vasoactive substance (possibly involved in the aetiologyof cerebral arterial spasm) in cerebrospinal fluid from patientswith subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry39: 756-766, 1976

102. Brandt L, Ljunggren B, Anderson KE, Hindfelt B, Teasdale G:Vasoconstrictive effects of human post-hemorrhagic cerebrospi-nal fluid on cat pial arterioles in situ. J Neurosurg 54: 351-356,1981

103. Okwuasaba FK, Weir BKA, Cook DA, Krueger CA: Effects ofvarious intracranial fluids on smooth muscle. Neurosurgery 9:402-406, 1981

104. Sasaki T, Murota S, Wakai S, Asano T, Sano K: Evaluation ofprostaglandin biosynthetic activity in canine basilar artery follow-ing subarachnoid injection of blood. J Neurosurg 55: 771-778,1981

105. Maeda Y, Tani E, Miyamoto T: Prostaglandin metabolism inexperimental cerebral vasospasm. J Neurosurg 55: 779-785,1981

106. Walker V, Pickard JD, Smythe P, Eastwood S, Perry S: Effects ofsubarachnoid haemorrhage on intracranial prostaglandins. JNeurol Neurosurg Psychiatry 46: 119-125, 1983

107. Martin V, Villani GM, Jothianandan D, Furchgott RF: Selectiveblockade of endofhelium dependent and glyceral-trinitrate in-duced relaxation by hemoglobin and methylene blue in the rabbitaorta. J Pharmacol Exp Ther 232: 708-716, 1985

108. Furchgott RF, Cherry PO, Zawadzki JV, Jothianandan D: Endo-thelial cells as mediators of vasodilation of arteries. J CardiovascPharmacol 6: S336-S343, 1984

109. Liszczak TM, Varsos VG, Black P, Kistler JP, Zervas NT: Cere-bral arterial constriction after experimental subarachnoid hemor-

by guest on June 15, 2018http://stroke.ahajournals.org/

Dow

nloaded from

570 STROKE V O L 16, No 4, JULY-AUGUST 1985

rhage is associated with blood components within the arterialwall. J Neurosurg 58: 18-26, 1983

110. LeeTJF, Mcllhany MP, Sarwinski S: Erythocyte extracts enhanceneurogenic vasoconstriction of dog cerebral arteries in vitro. JCereb Blood Flow Metab 4: 474-476, 1984

111. Fox PL, Dicoleto PF. Regulation of production of a PDGF-likeprotein by cultured bovine aortic endothelial cells. J Cell Phys121: 298-308. 1984

112. Schwartz SM, Ross R: Cellular proliferation in atherosclerosisand hypertension. Progress in Cardiovascular Diseases 26: 355-372, 1984

113. Pelletieri L, Carlson CA, Lindholm L: Is the vasospasm followingsubarachnoid hemorrhage an immunoreactive disease? Experien-tia 15: 1170-1171, 1981

114. Ryan US: Immunological properties of endothelial cells. Journalof the Society for Artificial Internal Organs, 1985 (in press)

115. Ryan US: Endothelial cells and inflammation. Clinics in Labora-tory Medicine 3(4): 577-599, Dec. 1983

116. Weir BKA, Okwuasaba FK, Cook DA, Krueger CA: Pharmacol-ogy of Vasospasm-Effects of various agents including blood onisolated cerebral arteries. In Wilkins RH (ed): Cerebral ArterialSpasm. Baltimore, William & Wilkins, 1980, pp 237-243

117. Chyatte D, SundtT: Cerebral vasospasm after subarachnoid hem-orrhage. Mayo Clin Proc 59: 498-505, 1984

118. Mizukami M, Kawase T, Tazawa T, Nagata K, Yunoki K, Yo-shida Y: Hypothesis and clinical evidence for the mechanism ofchronic cerebral vasospasm after subarachnoid hemorrhage. InWilkins RH (ed): Cerebral Arterial Spasm. Baltimore, Williams& Wilkins, 1980, pp 97-106

119. Yasargil MG. In Microneurosurgery Vol. 1. New York, GeorgThieme Verlag, 1984, p 344

120. Hughes JT, Schianchi PM: A histological study at necropsy ofblood vessels in cases of subarachnoid hemorrhage. J Neurosurg48: 515-525, 1978

121. Yamashita T, Yamamota S: Cerebral artery pathology in experi-mental subarachnoid hemorrhage. J Neurosurg 58: 843-850,1983

122. Crompton MR: The pathogenesis of cerebral infarction followingthe rupture of cerebral berry aneurysms. Brain 87: 491-510, 1964

123. White RP: Multiple origins of cerebral vasospasm. In Cerehro-vascular Diseases. Price TR, Nelson E (ed), New York, RavenPress, 1979, pp 307-319

124. White RP, Robertson JT: Comparison of piroxicam, medofena-mate, ibuprofen, aspirin, and prostacyclin efficacy in a chronicmodel of cerebral vasospasm. Neurosurgery 12: 40-46, 1983

125. Chyatte D, Rusch N, Sundt TM Jr: Prevention of chronic experi-mental cerebral vasospasm with ibuprofen and high-dose methyl-prednisolone. J Neurosurg 59: 925-932, 1983

126. Janoffa A, Carp H: Proteases, anti-proteases and oxidants: Path-ways of tissue injury during inflammation. In Monographs inPathology, vol 23. Majno G, Cotran R. Kaufman N (ed). Balti-more, Williams & Wilkins, 1982, pp 62-82

127. Cotran R: Endothelium and inflammation. In Monographs in Pa-thology, vol 23. Majno G, Cotran R, Kaufman N (ed), Baltimore,Williams and Wilkins, 1982, pp 18-37

128. Pinckard RN: The new chemical mediators of inflammation. InMonographs in Pathology, vol 23. Majno G, Cotran R, KaufmanN (ed), Baltimore, Williams & Wilkins. 1982, pp 38-52

129. Dujovny M, Kaufman HH, KassoskyN, HurtelonMS, Miller M,Camel PC: Morphology of the subarachnoid space after subarach-noid hemorrhage in Wilkins RH (ed). Cerebral Arterial Spasm.Baltimore, Williams & Wilkins, 1980, pp 139-143

130. Sasaki T, Kassell NF, Yamashita M, Fujiwara S, Zuccarello M:Barrier disruption in the major cerebral arteries following experi-mental subarachnoid hemorrhage. J Neurosurg 1985 (in press)

131. Fox JL, Ko JP: Cerebral vasospasm: A clinical observation. SurgNeurol 10: 269-275, 1978

132. Hirata Y, Matsukado Y, Fukumura A: Subarachnoid enhance-ment secondary to subarachnoid hemorrhage with special refer-ence to the clinical significance and pathogenesis. Neurosurgery11: 367-371, 1982

133. Tazawa T, Mizukami M, Kawase T, Usami T, Togashi O, HyodoA, Eguchi T: Relationship between contrast enhancement on com-puted tomography and cerebral vasospasm in patients with sub-arachnoid hemorrhage. Neurosurgery 12: 643-648, 1983

134. Doczi T, Ambrose J, O'Laoire S: Significance of contrast en-hancement in cranial computerized tomography after subarach-noid hemorrhage. J Neurosurg 60: 335-342, 1984

135. Holmsen H: Platelet secretion. In Hemostasis and Thrombosis.Colman R, Hirsh J (ed), Philadelphia, LP Lippincott, 1982, pp390-403

136. Mustard JF, Kinlough-Rathbone R, Packham M: In Hemostasisand Thrombosis. Colman R, Hirsh J (ed), Philadelphia, LP Lip-pincott, 1982, pp 703-715

137. Garland CJ, Keatinge WR. Constrictive actions of ACH-5-HTand histamine on bovine coronary artery inner and outer muscle. JPhysiol 327: 363-376, 1982

138. Peterson JW, Bun T, Cardia GJ, Ronner SF, Charnvis K, ZervasNT: Basilar arterial membrane is depolarized during cerebralvasospasm due to subarachnoid hemorrhage. Stroke 16(1): 138,1985 (abstr)

139. Grottendorst GR, Sippa HES, Kleinman HK, Martin GR: Attach-ment of smooth muscle cells to collagen and their migration to-ward platelet derived growth factor. Proc Nat Acad Sci 78:S669-S672, 1981

140. White RP, Robertson JT: Role of plasmin, thrombin and anti-thrombin as etiological factors in delayed cerebral vasospasm.Neurosurg 16(1): 27-35, 1985

141. Boullin DJ: Assessment of animal models. In Wilkins RH (ed):Cerebral Arterial Spasm. Baltimore, Williams & Wilkins. 1980,pp 291-293

142. White RP: Vasospasm. I. Experimental Findings. In Fox JL (ed):Intra-Cranial Aneurvsms Vol I. Springer-Verlag, 1983, pp218-249

143. Simeone FA, Vinall PE: Evaluation of animal models of cerebralvasospasm. In Wilkins RH (ed): Cerebral Arterial Spasm. Balti-more, Williams & Wilkins, 1980, pp 284-286

144. Fraser RAR. Cerebral vasospasm: After 15 years in the laborato-ry. In Wilkins RH (ed): Cerebral Arterial Spasm. Baltimore,Williams & Wilkins, 1980, pp 187-210

145. Duff TA, Feilbach JA, Scott G: Ultrastructural evidence of arteri-al denervation following experimental subarachnoid hemorrhage.Stroke 16(1): 142, 1985 (abstr)

146. Espinosa F, Weir B, Boisvert D, Overton T, Caston W. Chroniccerebral vasospasm after large subarachnoid hemorrhage in mon-keys. J Neurosurg 57: 224-232, 1982

147. Peerless SJ. Fox AJ, Komatsu K, Hunter IG: Angiographic studyof vasospasm following subarachnoid hemorrhage in monkeys.Stroke 13: 473-479, 1982

148. Varsos VG, Liszczak TM, Han DH, Kistler JP, Vielma J, BlackPM, Heros RC, Zervas NT: Delayed cerebral vasospasm is notreversible by aminophylline, nifedipine, or papaverine in a "two-hemorrhage" canine model. J Neurosurg 58: 11-17, 1983

149. Chyatte D, Sundt TM Jr: Response of chronic experimental cere-bral vasospasm to methylprednisolone and dexamethasone. JNeurosurg 60: 923-926. 1984

150. Echlin FA: Vasospasm and focal cerebral ischemia. An experi-mental study. Arch Neurol Psychiat (Chicago) 47: 77-96, 1942

151. Wellum GR, Irvine TW, Zervas NT: Dose responses of cerebralarteries of the dog. rabbit, and man to human hemoglobin in vitro.J Neurosurg 53: 486-490, 1980

152. Hart MN: Morphometry of brain parenchymal vessels followingsubarachnoid hemorrhage. Stroke 11: 653-55, 1980

153. Baumbach GL, Heistad DD: Effect of sympathetic stimulationand changes in arterial pressure on segmental resistance of cere-bral vessels in rabbits and cats. Circ Res 52: 527-533, 1983

154. Grubb RL Jr, Raichle ME, Eichlins JO, Gado MH: Effects ofsubarachnoid hemorrhage on cerebral blood volume, blood flow,and oxygen utilization in humans. J Neurosurg 46: 446-453,1977

155. Kassell NF, Boarini DJ: Timing of aneurysm surgery. In Neuro-surgery, vol 2. Wilkins RH, Rengachary SS (ed). New York,McGraw Hill, 1985, pp 1363-1366

156. Pickard JD, Read DH, Lovick AHJ: Pre-operative assessment ofcerebrovascular reactivity following subarachnoid hemorrhage —clinical correlations. Second International Symposium: "CerebralAneurysm Surgery in the Acute Stage", Graz, Austria, Sept 1984,p 51 (abstr)

157. Kapp JP, Neill WR. Neill CL, Hodges LR, Smith RR: The threephases of vasospasm. Surg Neurol 18: 40-45, 1982

by guest on June 15, 2018http://stroke.ahajournals.org/

Dow

nloaded from

CEREBRAL VASOSPASM/K«.v.v<?// el al 571

158. Suzuki S. Suzuki M. Iwabuchi T. Kamata Y: Role of multiplecerebral microthrombosis in symptomatic vasospasm — with acase report. Neurosurg 13(2): 199-203. 1983

159. Under M: Inhibition by dipyradimolc of cerebral vasospasm in-duced in vitro by whole blood. J Neurosurg 58(3): 352-5. 1983

160. Wilkins RH: Attempted prevention or treatment of intracranialarterial spasm: A survey. In Wilkins RH (ed): Cerebral ArterialSpasm. Baltimore. Williams & Wilkins. 1980. pp 542-555

161. Mizukami M. Kawase T. Usami T. Tazawa T: Prevention ofvasospasm by early operation with removal of subarachnoidblood. Neurosurgery 10: 301-307. 1982

162. Tancda M: Effect of early operation for ruptured ancurvsm onprevention of delayed ischemic symptoms. J Ncurosura 57:622-628. 1982

163. Sano K. Saito I: Early operation and washout of blood clots forprevention of cerebral vasospasm. In Wilkins RH (ed): CerebralArterial Spasm. Baltimore. Williams & Wilkins. 1980. pp510-513

164. Peterson EW. Choo SH. Lewis AJ. Lach B. Bormanis J: Lysis ofblood clot and experimental treatment of subarachnoid hemor-rhage. In Wilkins RH (ed): Cerebral Arterial Spasm. Baltimore.Williams & Wilkins. 1980. pp 625-627

165. Hashi K. AoyamaT. Nin K. ShimotakeT: Further trial of cister-nal clot removal for severe subarachnoid hemorrhage. SecondInternational Symposium. "Cerebral Ancurysm Surgery in theAcute Stage." Graz. Austria. Sept 1984. p 221 (abslr)

166. Drake CG: Management of cerebral ancurysm. Stroke 12:273-283. 1981

167. Ohta H. Ito Z. Yasui N. Suzuki A: Extensive evacuation of sub-arachnoid clot for prevention of vasospasm . . . effective or not?Acta Neurochir (Wien) 63: 111-116. 1982

168. Ljunggren B. Brandt L. Kagstrom E. Sundbarg G: Results ofearly operations for ruptured aneurysms. J Neurosum 54:473-479. 1981

169. Shiobara R. Kawase T. Toya S. Ebato K. Miyahara Y: "Scavcn-gery Surgery" for subarachnoid hemorrhage (II) — Continuousventriculo-cisternal perfusion by use of artilicial ccrebrospinalfluid with urokinase. Second International Symposium, "CerebralAneurysm Surgery in the Acule Stage. Graz. Austria. Sept 1984.p 121 (abstr) "

170. Saito I. Segawa H. Nagayama I. Kitamura K. Nihci H: Preventionof postoperative vasospasm by cisternal injection. Second Inter-national Symposium. "Cerebral Aneurysm Surgery in the AcuteStage." Graz. Austria. Sept 1984. p 171 (abstr)

171. Allen GS. Banghart SB: Cerebral arterial spasm: Part 9. In vitroeffects of nifedipine on serotonin-, phcnylephrinc-. and potas-sium-induced contractions of canine basilar and femoral arteries.Neurosurgery 4: 37-42. 1979

172. Brandt L. Andcrsson KE. Edvinsson L. Ljunggren B: Effects ofextracellular calcium and of calcium antagonists on the contractileresponses of isolated human pial and mesenteric arteries. J CerebBlood Flow Metab 1: 339-347. 1981

173. KazdaS, Toward R: Nimodipinc: a new calcium antagonistic drugwith a preferential cerebrovascular action. Acta Neurochir (Wien)63: 259-265, 1982

174. Shimizu K, OhtaT, Toda N: Evidence for greater susceptibility ofisolated dog cerebral arteries to Ca + + antagonists than peripheralarteries. Stroke 11: 261-266. 1980

175. Hayashi S. Toda N: Inhibition by Ca~ + . verapamil and papaver-ine of Ca2 +-induced contractions in isolated cerebral and periph-eral arteries of the dog. Brit J Pharmacol 60: 35-43. 1977

176. McCalden TA. Bevan JA: Sources of activator calcium in therabbit basilar artery. Am J Physiol 241: H129-H133. 1981

177. Auer LM, Ito Z. Suzuki A. Ohta H: Prevention of symptomaticvasospasm by topically applied nimodipine. Acta Neurochir(Wien) 63: 297-302. 1982

178. Barry KJ, Mikkelsen RB. Shucart W. Keough EM. Garvis V:Isolation and characterization of calcium-accumulating sub-cellu-lar membrane fractions from cerebral arteries. J Neurosurg 62:729-736, 1985

179. Allen GS, Ahn HS, Preziosi TJ. Battye R, Boone SC, Chou SN.Kelly DL, Weir BK, Crabbe RA. Lavik PJ. Rosenbloom SB,Dorsey FC, Ingram CR, Mellits DE. Bertsch LA, Boisvery DPJ,Hundley MB, Johnson RK. Strom JA. Transou CR: Cerebralarterial spasm — a controlled trial of nimodipine in patients with

subarachnoid hemorrhage. N Engl J Mcd 308: 619-624. 1983180. Towart R: The pathophvsiology of cerebral vasospasm. and phar-

macological approaches to its management. Acta Neurochir(Wien)~63: 253-258. 1982

181. Levin RM. Weiss B: Selective binding of antipsychotics and otherpsychoactive agents to the calcium-dependent activator of cyclicnucleotide phosphodiesterase. J Pharmacol Exp Ther 208:454-459. 1979

182. Blaumanis OR. Grady PA: Experimental cerebral vasospasm: res-olution by chlorpromazine. Sure Neurol 17: 263-268. 1982

183. Nakano M. Tani E. Fukumori T. Yokota M: Effects of chlorpro-mazine on experimental delayed cerebral vasospasm. J Neurosurg61: 857-863. 1984

184. Peterson JW. Adams JF. Zervas NT: Calmodulin antagonism canprevent and relieve delayed cerebral vasospasm in two hemor-rhage canine model. Fifty-Sixth Scientific Sessions of the Ameri-can Heart Assoc. Anaheim Convention. Circulation 68 (sup 3):171. 1983 (abstr)

185. Gavras H. Andrews P. Papadakis N: Reversal of experimentaldelayed cerebral vasospasm by angiotensin-converting enzymeinhibition. J Neurosurg 55: 884-888. 1981

186. Andrews P. Papadakis N. Gavras H: Reversal of experimentalacute cerebral vasospasm by angiotensin converting enzyme inhi-bition. Stroke 13(4): 480-483." 1982

187. Sasaki T. Wakai S. Asano T. Takakura K. Sano K: Prevention ofcerebral vasospasm after SAH with a thromboxane synthetaseinhibitor OKY-1581. J Neurosurg 57: 74-82. 1982

188. Chan RC. Durity FA. Thompson GB. Nugent RA. Kendall M:The role of the prostacyclin-thromboxane system in cerebral vaso-spasm following induced subarachnoid hemorrhage in the rabbit.J Neurosurg 6V. 1120-1128. 1984

189. Tani E. Maeda Y. Fukumori T. Nakano M. Kochi N. MorimuraT. Yokota M. Matsumoto T: Effect of selective inhibitor ofthromboxane A2 synthetase on cerebral vasospasm after earlysurgery. J Neurosurg 61: 24-29. 1984

190. Quintana L. Kouda R. Ishibashi Y. Yoshimoto. Suzuki J: Theeffect of prostacyclin on cerebral vasospasm. An experimentalstudy. Acta Neurochir (Wien) 62: 187-193. 1982

191. Fukumori T. Tani E. Maeda Y. Sukenaga A: Effects of prostacy-clin and indomethacin on experimental delayed cerebral vaso-spasm. J Neurosurg 59: 829-834, 1983

192. Hashi K. Matsuoka T. Tanaka K. Ohkawa N: Treatment of cere-bral vasospasm with large doses of hydrocortisone. In Wilkins RH(ed): Cerebral Arterial Spasm. Baltimore. Williams & Wilkins,1980. pp 611-618

193. Oba M. Mizoi K. Fujimoto S. Yashimoto T. Suzuki J: Effect ofposlischemic administration of mannitol. Vitamin E. dexametha-sone and perfluorochemicals on cerebral ischemia. An experi-mental study. In Spetzler RF. Carter LP, Selman WR. Martin NA(ed). Cerebral Revascularizatioit for Stroke. New York, ThiemeStratton 1985. pp 267-274

194. Kato Y. Sano H, Katada T. Kanno T: Experimental and clinicalstudy in the use of intrathecal a-tocopherol in vasospasm. SecondInternational Symposium, "Cerebral Aneurysm Surgery in theAcute Stage." Graz. Austria, Sept 1984. p 179 (abstr)

195. Dale J. Landmark KH. Myhre E: The effects of nifedipine. acalcium antagonist, on platelet function. Am Heart J 105:103-105. 1983

196. Boulin DJ: Potential use of prostacyclin in the treatment of vaso-spasm. In Wilkins RH (ed) Cerebral Arterial Spasm, Baltimore.Williams & Wilkins, 1980, pp 533-539

197. Brown FD. Hanlon K, Mullan S: Treatment of aneurysmal hemi-plegia with dopamine and mannitol. J Neurosurg 49: 525-529,1978

198. Giannotta SL. McGillicuddy JE, Kindt GW: Diagnosis and treat-ment of postoperative cerebral vasospasm. Surg Neurol 8:286-290. 1977

199. Pritz MB, Giannotta SL. Kindt GW. McGillicuddy JE. DragerRL: Treatment of patients with neurological deficits associatedwith cerebral vasospasm by intravascular volume expansion.Neurosurgery 3: 364-368. 1978

200. McMurty JG, Pool JL. Nova HR: The use of rheomecrodex in thesurgery of intracranial aneurysms. J Neurosurg 26: 218-222,1967

201. Boscherstein FK, Reilly JA, Yahr MD, Correll JW: Effect of low

by guest on June 15, 2018http://stroke.ahajournals.org/

Dow

nloaded from

572 STROKE V O L 16, No 4, JULY-AUGUST 1985

molecular weight dextran on cortical blood flow. Arch Neurol 14:288-293, 1966

202. Wood JH, Simeone FA, Kron RE, Litt M: Rheological aspects ofexperimental hypervolemic hemodilution with low molecularweight dextran: relationship of cortical blood flow, cardiac out-put, and intracranial pressure to fresh blood viscosity and plasmavolume. Neurosurgery 11: 739-753, 1982

203. Suzuki J, Yoshimoto T: The effect of mannitol in prolongation ofpermissible occlusion time of cerebral artery — clinical data ofaneurysm surgery. Neurosurg Rev 1: 13-19, 1979

204. Little JR, Slugg RM, Latchaw JP Jr, Lesser RP: Treatment ofacute focal cerebral ischemia with concentrated albumin. Neuro-surgery 9: 552-558, 1981

205. Auer LM: Pial arterial vasbdilatation by intravenous nimodipinein cats. Drug Research 31: 1423-1425, 1981

206. Moncada S, Gryglewski R, Bunting S, Vane JR: An enzymeisolated from arteries transforms prostaglandin endoperoxides toan unstable substance that inhibits platelet aggregation. Nature263: 663-665, 1976

207. Boullin DJ, Bunting S, Blaso WP, Hunt TM, Moncada S: Re-sponses of human and baboon arteries to prostaglandin endoper-oxides and biologically generated and synthetic prostacyclin: theirrelevance to cerebral arterial spasm in man. Br J Clin Pharmacol7: 139-147, 1979

208. Burke AM, Quest DO, Chien S, Cerri C: Effects of mannitol onblood viscosity. J Neurosurg 55: 550-553, 1981

209. Kee DB, Wood JH: Rheology of the cerebral circulation. Neuro-surg 15: 125-131, 1884

210. Heyman A, Saltzman HA, Whalen RE: The use of hyperbaricoxygenation in the treatment of cerebral ischemia and infarction.Circ 33/34 (suppl): 20-27, 1966

211. Handa H, Nagasawa S, Yonekawa Y, Narvo Y, Oda Y: Newtreatment of cerebral vasospasm with fluosol-Da 20%: Protectiveeffect on cerebral ischemia and change of cerebral blood flow(CBF). Prog Cir Biol Res 122: 299-306, 1983

212. Naito R, Yokoyama K: Physical and chemical properties of fluo-sol-DA after mixing with annex solutions. In Naito F, YokoyamaK (eds): Perfluorochemical Blood Substitutes. Osaka, Japan,Green Cross Corporation, 1978, pp 73-79

213. Tranmer BI, Gross CE, Kindt GW, Adey GR: The effect ofpulsatile versus non-pulsatile blood flow in the treatment of ische-mic stroke. Surg Forum, 1985 (in press)

214. Kassell NF, Peerless SJ, Durward QJ, Beck DW, Drake CG,Adams HP: Treatment of ischemic deficits from vasospasm withintravascular volume expansion and induced arterial hyperten-sion. Neurosurgery 11: 337-343, 1982

215. Flower RG: Macrocortin and the antiphospholipase proteins. InWeissman G (ed) Advances in Inflammation Research, vol 8,New York, Raven Press, 1984, pp 1-34

216. Schanne FAX, Kane AB, Young EE, Farber JL: Calcium depend-ence of toxic cell death: a final common pathway. Science 206:700-702, 1979

217. Kassell NF, Peerless SJ, Drake CG, Boarini DJ, Adams HP:Treatment of ischemic deficits from cerebral vasospasm with highdose barbiturate therapy. Neurosurg 7: 593-597, 1980

by guest on June 15, 2018http://stroke.ahajournals.org/

Dow

nloaded from

N F Kassell, T Sasaki, A R Colohan and G NazarCerebral vasospasm following aneurysmal subarachnoid hemorrhage.

Print ISSN: 0039-2499. Online ISSN: 1524-4628 Copyright © 1985 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Stroke doi: 10.1161/01.STR.16.4.562

1985;16:562-572Stroke. 

http://stroke.ahajournals.org/content/16/4/562World Wide Web at:

The online version of this article, along with updated information and services, is located on the

  http://stroke.ahajournals.org//subscriptions/

is online at: Stroke Information about subscribing to Subscriptions: 

http://www.lww.com/reprints Information about reprints can be found online at: Reprints:

  document. Permissions and Rights Question and Answer available in the

Permissions in the middle column of the Web page under Services. Further information about this process isOnce the online version of the published article for which permission is being requested is located, click Request

can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office.Stroke Requests for permissions to reproduce figures, tables, or portions of articles originally published inPermissions:

by guest on June 15, 2018http://stroke.ahajournals.org/

Dow

nloaded from