Acute management of ischaemic stroke 7

ConclusionEarly initiation of novel treatments (thrombo-lytics and neuroprotectants) in patients withacute ischaemic stroke is likely to improve theoutcome for these patients. However, both ofthese types of treatment must be given as earlyas possible for optimal effect and safety. Whilethe administration of thrombolytics requires adefinitive diagnosis, it is hoped that in thefuture, it may be possible to treat patients withneuroprotective treatments before the patientarrives in hospital. In order for this to happen,emergency service personnel should be able toevaluate a stroke patient promptly, and beaware of the need to treat stroke asan emergency. Additionally, the generalpublic needs to be educated to recognise thesigns and symptoms of stroke and to reactquickly to them by calling the emergencynumber.

1 Thorvaldsen P, Asplund K, Kuulasmaa K, et al. Stroke inci-dence, case fatality and mortality in the WHO MONICAproject. World Health Organization monitoring trends anddeterminants in cardiovascular disease. Stroke1995;26:361-7.

2 Spitzer K, Becker V, Thie A, et al. The Hamburg stroke databank: goals, design and preliminary results. Jf Neurol 1989;236:139-44.

3 Adams HP Jr, Brott TG, Furlan AJ, et al. Guidelines forthrombolytic therapy for acute stroke: a supplement to theguidelines for the management of patients with acuteischemic stroke. A statement for healthcare professionalsfrom a special writing group of the Stroke Council, Ameri-can Heart Association. Stroke 1996;27:1711-18.

4 Solis 0, Robertson G, Taveras J, et al. Cerebral angiographyin acute cerebral infarction. Rev Interam Radiol 1979;2: 19-25.

5 Allen C. Clinical diagnosis of acute stroke syndrome. Q JMed 1983;42:515-23.

6 Poungvarin N, Viriyavejakul A, Komontri C. Siriraj strokescore and validation study to distinguish supratentorialintracerebral hemorrhage from infarction. BMJ7 1991;302:1565-7.

7 Jafar J, Crowell R. Focal ischemic thresholds. In: Wood J, ed.Cerebral blood flow. New York: McGraw-Hill, 1987:449-57.

8 Hacke W, Stingele R, Steiner T, et al. Crititcal care of acuteischemic stroke. Intensive Care Med 1995;21:856-62.

9 Astrup J, Siesjo BK, Symon L. Thresholds in cerebralischemia-the ischemic penumbra. Stroke 1981;12:723-5.

10 Caplan L. Reperfusion of ischemic brain: why and why not.In: Hacke W, del Zoppo G, Hirschberg M, eds. Thrombo-lytic therapy in acute ischemic stroke. Berlin: Springer, 1991:37-45.

1 1 Adams HJ, Brott T, Furlan A, et al. Guidelines for thrombo-lytic therapy for acute stroke: a supplement to theguidelines for the management of patients with acuteischemic stroke. A statement for healthcare professionalsfrom a special writing group of the stroke council,American Heart Association. Stroke 1996;27: 1711-8.

12 The RANTAS Investigators. A randomized trial oftirilazad mesylate in patients with acute stroke (RANT-TAS). Stroke 1996;27:1453-8.

13 The European Ad Hoc Consensus Group. Europeanstrategies for early intervention in stroke. CerebrovascularDisease 1996;6:315-24.

14 Alberts M, Perry A, Dawson D, et al. Effects of public andprofessional education on reducing the delay in presenta-tion and referral of stroke patients. Stroke 1992;23:352-6.

15 Kothari R, Barsan W, Brott T, et al. Frequency and accuracyof prehospital diagnosis of acute stroke. Stroke 1995;26:937-41.

16 Lott C, Hennes H, Dick W. Prehospital diagnosis in strokepatients-differentiation between cerebral ischemic eventsand hemorrhage. Intensive Care Med 1996;22 (suppl1):S96.

17 The American-Canadian Co-Operative Study Group. Pre-santine aspirin trial in cerebral ischaemia. Part II: endpointresults. Stroke 1985;16:406-15.

18 Bronstein KS, Chadwick LR. Ticlopidine hydrochloride: itscurrent use in cerebrovascular disease. Rehabilitation Nurs-ing 1994;19:17-20.

19 Hacke W, Kaste M, Fieschi C, et al. Intravenous thromboly-sis with recombinant tissue plasminogen activator for acutehemispheric stroke. The European Cooperative AcuteStroke Study (ECASS).JAMA 1995;274:1017-25.

20 National Institute of Neurological Disorders and Strokert-PA Stroke Study Group. Tissue plasminogen activatorfor acute ischaemic stroke. NEnglJ'Med 1995;333:1581-7.

21 Hommel M, Biossel P, Cornu E, et al. for the MAST StudyGroup. Termination of trial of streptokinase in severe acuteischaemic stroke. Lancet 1994;345:57.

22 Multicenter Acute Stroke Trial Italy (MAST-I). Rand-omized controlled trial of streptokinase, aspirin and combi-nation of both in treatment of acute ischaemic stroke. Lan-cet 1995;346:1514.

23 Donnan GA, Davis SM, Chambers BR, et al. Trials of strep-tokinase in severe acute ischaemic stroke. Lancet 1995;345:578-9.

24 Walghren NG, MacMahon DG, De Keyser J, et al for theINWEST Study Group. Intravenous Nimodipine WestEuropean Stroke Trial of nimodipine in the treatment ofacute ischaemic stroke. Cerebrovascular Disease 1994;4:197-203.

25 Muir KW, Lees KR. Clinical experience with excitatoryamino acid antagonist drugs. Stroke 1995;26:503-13.

26 MacDonald JW, Silverstein FS, Johnston MV. Magnesiumreduces N-methyl-D-aspartate (NMDA)-mediated braininjury in perinatal rats. Neurosci Lett 1990;109:234-8.

27 Young W, Wojack JC, De Crescito W 21-aminosteroidreduces ion shift in oedema in the rat middle cerebralocclusion model of regional ischaemia. Stroke 1988;9:1013-19.

28 RANTTAS Investigators. Randomised trial of tirilizad inacute stroke (RANTTAS) by the RANTAS investigators,the neuroclinical centre, University of Charlottesville, VA,and the North American RANTTAS participants. Stroke1996;27: 164 (abst).

29 Diener H, Hacke W, Hennerici M. Lubeluzole in acuteischemic stroke: a double-blind placebo controlled phase IItrial. Stroke 1996;27:76-81.

Recent advances in the acute management ofischaemic stroke

Michael Roberts, Geoff Hughes

Department ofEmergency Medicine,Wellington Hospital,Riddiford Street,Wellington, NewZealandM RobertsG Hughes

Correspondence to:Mr Roberts, Registrar(e-mail:phillifam@xtra.co.nz).

Accepted 7 August 1998

Stroke is the third commonest cause of deathand the commonest cause of adult disability inthe western world. Approximately 1.5 millionpatients in Europe and America suffer acutestroke each year' and 85% of these are ischae-mic. This is an enormous burden to patients,their families, and also to health care systems.Although the incidence of stroke has declinedin recent years,2 it is likely to become moreprevalent in the future as the population ages.

Recent licensing of the thrombolytic agent,recombinant tissue plasminogen activator (rt-PA) in the United States for treatment of

selected stroke patients has focused attentionon active stroke management. However therestoration of blood flow to ischaemic brain isonly one of several approaches currently beinginvestigated to improve stroke outcome. Ad-vances in the understanding and manipulationof the cellular derangements which occur inthe ischaemic brain offer other possibilities foractive treatment. Development of investiga-tions which differentiate between ischaemicand infarcted tissue will allow new therapies tobe directed towards those patients most likelyto benefit.

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Ca2+NMDA

~~ euronal cell bodyNMDA / ;C +

Axon channelterminal G Na a2 , 2+ \ Voltage

Ca2+ Ca 2+ Vlae23 Goeozytec Phospholipases gated CaG roteolytic ~~~~~channel

enzymesG Protein Lipid peroxidation

degradation `\Free radical 'formation-, Membrane

destruction

Figure 1 Mechanism of neuronal death duringfocal brain ischaemia. Ca2` = intracellularfree calcium ion; G = glutamate; Na+ = oxidised sodium ion; NMDA =N-methyl-D-aspartate. (Reproducedfrom G WAlbers. Rationale for early intervention inacute stroke. Am J Cardiol 1997;80(4C):4D-1OD with permission from Excerpta MedicaInc.)

PathophysiologyBrain tissue is an energetic substrate whoserequirement for oxygen and glucose is nor-mally met by a cerebral blood flow of approxi-mately 50 ml/min/100 g of tissue. Cerebralperfusion below this level results in aberrationof neuronal function as detailed in table 1.

Following occlusion of a cerebral vessel, bythrombosis or embolism, blood flow to an areaof the brain is reduced. The affected brain hasa central area of infarction surrounded by an"ischaemic penumbra" of potentially salvage-able tissue.3 The two areas are not clearlydemarcated and the volume of potentiallysalvageable tissue is constantly declining ac-cording to the interaction between durationand severity of ischaemia.'At a cellular level hypoperfusion reduces the

supply of oxygen and glucose available for theaerobic production ofATP. Anaerobic metabo-lism provides inadequate levels of ATP tomaintain cellular function which is furthercompromised by lactic acid generation. Mem-brane pump failure results and causes a wave ofdepolarisation. This in turn stimulates amassive release of glutamate and other excita-tory neurotransmitters. The inability to removethese molecules from the synaptic cleft, an-other energy requiring process, causes theglutamate sensitive N-methyl-D-aspartate(NMDA) channels in the neuronal cell mem-brane to open and allow unrestricted influx ofsodium and calcium. Sodium draws water withit causing neurones to swell, and the calciuminflux activates proteolytic enzymes and li-pases, which in turn cause generation of freeradicals and prostaglandins. These changes,which lead to cellular death are summarised infig 1.

Ischaemic injury to vessels within the stroketerritory causes increased vascular permeabil-

Table 1 Brain ischaemic thresholds (reproducedfromIntensive Care Manual 1997, edited by TE Oh, withpermission from Butterworth Heinemann Ltd)

Cerebral bloodflow(mllminllOO g brain) Changes

50 Normal25-30 Abnormal EEG15-25 Isoelectric EEG10-15 Absent evoked potentials<10 Membrane failure<10 prolonged (min) Cell death

EEG = electroencephalogram.

ity in the hours following stroke. This cancause haemorrhagic transformation of inf-arcted tissue, varying in severity from smallpetechiae to large and clinically significantparenchymal haematomas. Haemorrhagictransformation is commonest in large volumelesions and in those of cardioembolic origin."6

Imaging in acute strokeComputed tomography is still considered thebest tool to differentiate ischaemic from haem-orrhagic stroke at the time of presentation,7 anecessity if thrombolytics or antithromboticsare used.8 Identification of hypodense areas onearly computed tomograms, suggesting sub-stantial areas of infarction,9 also helps to iden-tify those lesions most likely to undergo haem-orrhagic transformation. These patients are theones most likely to suffer intracranial haemor-rhage if thrombolysed."'While magnetic resonance imaging (MRI) is

reported to show ischaemic changes earlierthan can be demonstrated by computedtomography, it is less useful in making theessential distinction between ischaemic andhaemorrhagic stroke. It is also less available,more expensive, and more time consuming.Within these constraints the newer tech-

niques of MRI and MR spectroscopy with dif-fusion weighted imaging allow differentiationbetween infarcted and ischaemic tissue."When these imaging modalities are morewidely available they will permit patientselection for thrombolysis based on identifica-tion of potentially salvageable tissue ratherthan by application of a rigid time interval fromsymptom onset. The latter may excludepatients who could still benefit from treatmentand includes, and exposes to the risk of haem-orrhage, some patients with little salvageabletissue (see figs 2, 3, and 4).

Treatment optionsPotential treatments may be categorised bymechanism of action. Interventions such asthrombolytics and antithrombotics, which aimto improve blood supply to affected tissue, aredistinguished from neuroprotective agentswhich aim to reduce the damage caused byischaemia. An alternative classification differ-entiates simple, often inexpensive, interven-tions, which can be widely used after minimalinvestigation from treatments such as throm-bolysis, which are expensive and can only beused on a relatively small group of patientsafter intensive investigation.The first group may produce considerably

smaller percentage improvements in outcomebut their broad applicability may result in agreater overall benefit to populations. Recogni-tion of these differences'2 and the impact theyshould have on trial design has been clearlydefined. 13Many potential treatments require prompt

institution if they are to be helpful, and educa-tion of the public and the medical profession toexpedite hospitalisation of patients with strokewill become more important. Management ofpatients by dedicated stroke teams in their ownunits is also of proved benefit. "

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Figure 2 Computed tomogram showing acutehaemorrhagic stroke with surrounding oedema atfourhours after onset of symptoms.

Figure 3 Tl weighted MRI scan showing occipital infarctat eight hours after onset ofsymptoms.

General measures

Airway protection in patients with decreasedlevel of consciousness or absent gag reflex, cor-

rection of hypoxaemia and treatment ofhypoglycaemia or hyperglycaemia are all essen-tial. Relevant blood tests include full bloodcount to identify hyperviscosity states andthrombocytopenia and coagulation studies toexclude coagulopathy. Measurement of theerythrocyte sedimentation rate may identify a

Figure 4 T2 weightedMRI scan showing occipital infarctat eight hours after onset of symptoms.

vasculitis. Arterial blood gas estimation shouldbe performed if respiratory function may becompromised. An electrocardiogram should beobtained to identify a possible cardiac cause forstroke; atrial fibrillation and acute myocardialinfarction are both significant risk factors.Echocardiography may demonstrate valvarvegetations or mural thrombus if cardioem-bolic stroke is suspected. Basic nursing caresuch as preservation of skin integrity byprotection of pressure areas should receiveattention from the time of arrival at hospital.Brain injury is temperature sensitive and sotreatment of pyrexia and any underlying causeis recommended."5

Blood pressure controlAfter stroke normal autoregulatory mecha-nisms fail and cerebral perfusion is directlyrelated to mean arterial blood pressure. Atpresent there is no evidence from randomisedcontrolled trials that lowering blood pressure atany level is beneficial.'6 Current recommenda-tions are that hypertension should not betreated unless severe (systolic >220 mm Hg ordiastolic >130 mm Hg) so that unnecessarycerebral hypoperfusion can be avoided.'5 How-ever hypertension is a risk factor for haemor-rhagic transformation and trials of thrombo-lytic agents have set a lower threshold fortreatment or exclusion. In the National Insti-tute of Neurological Disorders and Stroke(NINDS) trial of rt-PA, for example, patientswhose blood pressure could not easily bebrought below 185 mm Hg systolic wereexcluded.'7 It must be emphasised that thesevaried parameters for treatment are not basedon evidence from controlled trials. These stud-ies remain to be performed.

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No studies have investigated the importanceof raising blood pressure in patients who arehypotensive at presentation. Theoretical con-siderations suggest that this should be expe-dited in order to improve cerebral perfusionpressure and this is the recommendation of theStroke Council of the American Heart Associ-ation in their guidelines on strokemanagement. 15

HaemodilutionIntentional haemodilution, which may beisovolaemic or hypervolaemic, is known toimprove oxygen delivery to peripheral tissuesand has been used since the 1 960s as atreatment for acute ischaemic stroke. As thepacked cell volume (PCV) is reduced oxygendelivery increases to a peak but then falls as theloss of oxygen carrying capacity outweighs thereduction in blood viscosity. The peak lies at aPCV of 0.30-0.33 in normal peripheral tissuesbut there is evidence that in brain tissue themaximum may be as high as 0.40-0.45.Formal analysis of the 15 randomised control-led trials available has shown no reduction inearly or late case fatality or functional outcomeand this once popular treatment is no longerrecommended.'8 However it should be notedthat in these studies patients were treated up to72 hours after onset of symptoms. There issome evidence from animal studies suggestingthat haemodilution performed within threehours of cerebral occlusion can significantlyalter infarct size.'9 Further studies are requiredin this area.

CorticosteroidsCerebral oedema is a significant cause of deathafter stroke both directly by reduction ofcerebral perfusion pressure and indirectly byinducing vasospasm. Cerebral oedema may bevasogenic (related to breakdown of the blood-brain barrier as in tumours) or cytotoxic(related to cell membrane dysfunction asoccurs in focal or generalised ischaemia).While corticosteroids have a proved role in themanagement of vasogenic oedema they are notof value in the predominantly cytotoxicoedema of acute stroke. Meta-analysis of avail-able trials has shown that their use confers nobenefit and that there is also possibly a higherfatality rate among patients receiving them.20

Antithrombotic and antiplateletaggregating drugsThese agents, which are extensively used in theprevention of ischaemic vascular events, haveyet to have their role fully established in acutestroke. The rationale for their use is clear-they should help to maintain or improveperfusion to the brain by halting the propaga-tion of thrombus or preventing recurrentthromboembolism. They may also reducemortality and morbidity by preventing com-mon complications of stroke such as deep veinthrombosis and pulmonary embolism.Heparin has been used widely in stroke

management over the past 50 years. Howeverin the 1994 guidelines on the management ofacute ischaemic stroke issued by the American

Heart Association'5 the available data regard-ing its efficacy and safety were considered suf-ficiently unclear that no recommendationcould be made about its use. Publication of theresults of the International Stroke Trial in early1997 has added clarification.2' A total of19 435 patients with ischaemic stroke wereallocated to receive within 48 hours ofsymptom onset either subcutaneous heparin(at a dose of 5000 or 12 500 IU) or placebo.The patients were also allocated, in a factorialdesign, to either receive aspirin or not. Thestudy showed no overall benefit at six monthsfor patients receiving heparin and demon-strated a significantly higher incidence of majorextracranial bleeds, more haemorrhagicstrokes, and more deaths or non-fatal strokeswithin 14 days for those patients allocated tothe higher dose of heparin. The investigatorsconcluded that if heparin were to be used inclinical practice the lower trial dose of 5000 IUtwice a day should not be exceeded. In thissubgroup there was a small but significantdecrease of 1.2% in the incidence of earlydeath or recurrent stroke without a significantincrease of serious extracranial bleeds. This hasprompted a recommendation for furtherstudies.22Data relating to the efficacy of aspirin were

analysed alone and, as previously planned,summated with the results of the ChineseAcute Stroke Trial.23 In this investigation21 106 patients with suspected acute ischae-mic stroke received within 48 hours ofsymptom onset either aspirin in a dose of 160mg/day or placebo, continued for up to fourweeks. Overall there was a small, but significantbenefit to treatment with 13 per 1000 fewerdead or dependent in the first weeks andmonths of follow up.Low molecular weight (LMW) heparins and

heparinoids, both experimentally and clini-cally, are associated with a lower risk of bleed-ing than unfractionated heparin. Extensiveinvestigations in prophylaxis of deep veinthrombosis shows them to be more effectiveand safer than heparin, aspirin, and anticoagu-lants.The LMW heparin Nadroparin was used in

two doses in the randomised, placebo control-led Hong Kong study.24 At six monthsunfavourable outcomes were reduced from65% in a placebo group to 52% in a low dosetreatment group and 45% in those patientsreceiving a higher dose of Nadroparin. Furthertrials are underway as they are for the LMWheparinoid Org 10172 which has shownencouraging results in pilot studies.25

ThrombolysisA variety of thrombolytic agents have beenstudied including streptokinase, urokinase, andt-PA using intravenous and intra-arterialroutes for administration. Common to all trialsis the frustration of finding the benefits ofreperfusion partially or totally negated by theincreased risk of intracranial haemorrhage.The high levels of technical involvement

associated with the intra-arterial route areresponsible for the small number of studies of

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Table 2 The results of the major clinical trials of intravenous thrombolysis so far completed. (Reproducedfrom MJ Alberts. Hyperacute stroke therapywith tissue plasminogen activator. Am J Cardiol 1997;80(4C):29D-34D with permissionfrom Excerpta Medica Inc)

Time limitfromStudy Drug(s) used Dose stroke case (h) No ofpatients Major results

European Cooperative t-PA 1.1 mg/kg, to 6 620 17.4% of patients were enrolled despite major protocolStroke Study (ECASS)'° maximum of 100 mg violations. Analysis of all patients showed no benefit.

Analysis of eligible patients ("target population")revealed significant modified rank in scale improvementin favor of t-PA treated patients (p=0.035); 20% rate ofICH.

National Institute of t-PA 0.9 mg/kg, to 1.5-3 624 Compared with placebo group, t-PA treated patients wereNeurological Disorders maximum of 90 mg > 30% more likely to have minimal or no disability at 3and Stroke (NINDS) months. Symptomatic ICH within 36 hours of strokert-PA Stroke Study17 occurred in 6.4% of t-PA treated patients and 0.6% of

placebo treated patients (p<0.001).Multicenter Acute Stroke SK 1.5 MU* 6 310 Stopped early. There was a high frequency of

Trial-Europe haemorrhagic events and deaths in SK treated patients.(MAST-E)28 At 6 months, survivors in SK group had greater

improvement in function and were less likely to beseverely disabled than placebo treated patients, butdifferences were not statistically significant.

Multicenter Acute Stroke SK-aspirin 1.5 MU SK; 300 6 622 Stopped early. There was a non-significant reduction inTrial-Italy (MAST-I)29 mg/day aspirin likelihood of death/disability after treatment with SK.

However, 10 day mortality and symptomatic ICH weresignificantly higher in patients treated with SK. Risk ofearly death or bleeding especially high when SK wascombined with aspirin.

Australian Streptokinase SK 1.5 MU 4 340 Stopped early. Treatment with SK showed no significantTrial (ASK)30 benefit over placebo. There was a non-significant trend

toward unfavourable outcomes in SK treated patients.

*Other drugs could be administered at the discretion of the individual investigator. Some patients received heparin.ICH = intracerebral haemorrhage; MU = million units; SK = streptokinase; t-PA = tissue plasminogen activator.

its efficacy in spite of the theoretical advantageof the lower required dose of thrombolytic.However promising results from the PROACTtrial26 using prourokinase by this route are

under further investigation in the PROACT 11trial.27The results of the major clinical trials of

intravenous thrombolysis so far completed are

summarised in table 2.10 17 28-30

Clearly the results of the NINDS trial are

encouraging with a total of 11-13 extrapatients per hundred treated having an excel-lent outcome with little or no neurologicaldeficit. This is in spite of a 6.4% rate of intrac-ranial haemorrhage as compared with 0.6% inthe placebo group. Failure of the other trials toshow benefit may be for many reasons. Differ-ent thrombolytics at different doses were usedand treatment was often initiated longer aftersymptom onset than in the NINDS studywhere although the exclusion time for treat-ment was three hours, 50% of patients were

receiving treatment less than 90 minutes afteronset of symptoms.

Critics of thrombolysis point out that the624 patients in the study were selected fromover 17 000 patients presenting with stroke atthe participating hospitals. Most of the exclu-sions were for late presentation in spite of an

education programme aimed to minimise thisproblem. This suggests that thrombolysis can-

not yet be considered a routine treatment,although this may change when the results offurther studies (ATLANTIS and ECASS 2) ofthe efficacy of rt-PA used up to six hours aftersymptom onset become available.

Neuroprotective agentsA very large number of agents which mightreduce the effects of ischaemia at a cellularlevel have been studied.3' Given the pivotal roleof the NMDA receptor in the cellular derange-

ments induced by ischaemia it is unsurprisingthat much attention has been focused on itsregulation.While many of the non-competitive NMDA

antagonists used have shown substantial ben-efit in terms of reducing infarct size in experi-mental models, they have been unsuitable forclinical use because of their side effects. Theyblock the NMDA receptor in a fashion similarto phencyclidine (angel dust) and can causeparanoia, hallucinations, agitation, or a de-crease in conscious level.32 One of these agents,Aptiganel, has relatively fewer side effects andafter encouraging results in a phase 11 study iscurrently under further investigation.33 A com-petitive blocker of the glycine regulatory site onthe NMDA receptor, ACEA-1201, has alsoshown significant benefit in early trials andappears to be free of significant unwantedeffects.34Of the agents working distant to the NMDA

receptor lubeluzole is perhaps the most prom-ising. Its mechanism of action involves bothinhibiting the increase in extracellular gluta-mate concentrations and also inhibiting thenitric oxide synthetase pathway, which by pro-duction of intracellular nitric oxide contributesto ischaemic induced neuronal death. It hasbeen evaluated in a clinical trial involving 232patients.35 Patients receiving a low dose oflubeluzole showed a very significant improve-ment in 28 day mortality compared withplacebo and functional outcome also appearedto be improved in survivors. However thesebenefits were not apparent in a higher dosegroup in which there was a significantly greater28 day mortality compared with the placebogroup. A larger trial of this drug is currentlyunderway.

ConclusionIt is clear that the active management of strokeis an emerging discipline with many potential

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therapies still at an experimental stage. Rigor-ous design and conduct of trials of these agentscan play a significant part in allowing thosetreatments of proved efficacy to reach clinicalpractice quickly.Although thrombolysis has only been shown

to be of benefit when started soon after symp-tom onset, the possibility of giving a neuropro-tectant drug early, perhaps in the pre-hospitalsetting, which will prolong the viability of theischaemic neurones until more definitive treat-ment can be given is one which considerablybroadens their applicability.Emergency physicians have a pivotal role in

expediting the imaging and treatment of acutestroke patients. Liaison with local colleagues toformulate policies on management is essential.As clear treatment guidelines become availableit is increasingly obvious that the necessity forurgent intervention will make the role of theemergency department a crucial one if out-comes are to be improved.

1 Sandercock PAG, Celani MG, Ricci S. The likely publichealth impact in Europe of simple treatment for acuteischaemic stroke. Cerebrovascular Disease 1992;2:236.

2 Whisnant JP. The decline of stroke. Stroke 1984;15:160-8.3 Heiss WD, Graft R. The ischaemic penumbra. Curr Opin

Neurol 1994;7:11-19.4 Baron JC, von Kummer R, del Zoppo GJ. Treatment of

acute ischemic stroke challenging the concept of a rigid anduniversal time window. Stroke 1995;26:2219-21.

5 Jorgensen L, Torvik A. Ischemic cerebrovascular diseases inan autopsy series, part II: prevalence, location, pathogen-esis, and clinical course of cerebral infarct. Neurological Sci-ence 1969;9:285-320.

6 LodderJ, Krijne-Kubat B, Broekman J. Cerebral hemor-rhagic infarction at autospy: cardiac embolic cause and therelationship to the cause of death. Stroke 1986;17:626-9.

7 Johnston KC, Haley EC Jr. Emergency imaging of the acutestroke patient. J Neuroimaging 1997;7: 111-17.

8 Adams HP, Brott TG, Furlan AJ, et al. Guidelines forthrombolytic therapy for acute stroke: a supplement to theguidelines for management of patients with acute ischemicstoke. Stroke 1996;27:1711-18.

9 Moulin T, Cattin F, Crepin-Leblond T, et al. Early CT signsin acute middle cerebral artery infarction: predictive valvefor subsequent infarct locations and outcome. Neurology1996;47:366-75.

10 Hacke W, Kasate M, Fiechi C, et al. Intravenous thromboly-sis with recombinant tissue plasminogen activator for acutehemispheric stroke. The European Cooperative AcuteStudy (ECASS)_.JAMA 1995;274: 1017-25.

1 1 Fisher M, Prichard JW, Warach S. New magnetic resonancetechniques for acute ischemic stroke. J7AMA 1995;274:908-11.

12 Sandercock P, Willems H. Medical treatment of acuteischaemic stroke. Lancet 1992;339:537-9.

13 Dorman PJ, Sandercock PAG. Considerations in the designof clinical trials of neuroprotective therapy in acute stroke.Stroke 1996;27: 1507-15.

14 Markku K, Heikki P, Seppo S. Where and how should eld-erly stroke patients be treated? A randomized trial. Stroke1995:26:249-53.

15 Adams HP Jr, Brott TG, Crowell RM, et al. Guidelines forthe managment of patients with acute ischaemic stroke. Astatement for healthcare professionals from a specialwriting group of the Stroke Council, American HeartAssociation. Stroke 1994;25:1901-14.

16 Blood pressure management in acute stroke. Part 1: assess-ment of trials designed to alter blood pressure. CochraneDatabase of Systematic Reviews.

17 Tissue plasminogen activator for acute ischemic stroke. TheNational Institute of Neurological Disorders and Strokert-Pa Stroke Study Group. NEnglJMed 1995;333:11581-7.

18 Asplund K, Israelsson K, Schampi I. Haemodilution inacute ischemic stroke. Cochrane Database of SystematicReviews.

19 Kiyoyuki Y, Camarata P, Spellman SR, et al. Optimal timingof hemodilution for brain protection in a canine model offocal cerebral ischemia. Stroke 1996;27:906-12.

20 Qizilbash N, Lewington SL, Lopez-Arrieta JM. Cortico-steroids following acute presumed ischaemic stroke.Cochrane Database of Systematic Reviews.

21 International Stroke Trial Collaboration Group. The Inter-national Stroke Trial (IST): a randomised trial of aspirin,subcutaneous heparin, both or neither among 19435patients with acute ischaemic stroke. Lancet 1997;349:1569-81.

22 Bousser MG. Aspirin or heparin immediately after stroke.Lancet 1997:349:1564-5.

23 CAST (Chinese Acute Stroke Trial) Collaborative Group.Randomised placebo-controlled trial of early aspirin use in20 000 patients with acute ischaemic stroke. Lancet1997;349: 1641-9.

24 Kay R, Wong KS, YuYL, et al. Low-molecular-weightheparin for the treatment of acute ischaemic stroke. N EnglJrMed 1995;333:1588-93.

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