multidisciplinary management and emerging therapeutic

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Lancet Neurol2010; 9: 50419

Departments of Neurology

(A A Rabinstein MD,

E F M Wijdicks MD) and

Neurosurgery(G Lanzino MD),

Mayo Clinic, Rochester, MN,

USA

Correspondence to:

Alejandro A Rabinstein, Mayo

Clinic, Department of Neurology,

W8B, 200 First Street SW,

Rochester, MN 55905, USA

[email protected]

Multidisciplinary management and emerging therapeutic

strategies in aneurysmal subarachnoid haemorrhageAlejandro A Rabinstein, Giuseppe Lanzino, Eelco F M Wijdicks

The management of patients with aneurysmal subarachnoid haemorrhage demands expertise to anticipate, recognise,and promptly treat the many neurological and systemic complications. For this reason, these patients are best caredfor in high-volume medical centres with multidisciplinary teams and should preferably be treated in a specialisedintensive care unit. Endovascular occlusion and surgical clipping provide complementary alternatives for thetreatment of aneurysms. Perfusion scans are redefining the way we detect delayed ischaemia as a growing body ofevidence indicates that monitoring vessel diameter is insuffi cient to prevent cerebral infarctions. Statins, endothelinantagonists, and magnesium sulfate infusion are among the novel strategies being tested for neuroprotection andattenuation of vasospasm. The effectiveness of these treatments is supported by strong experimental data and theyrepresent a new generation of therapeutic options developed from the understanding that vasospasm is primarilycaused by endothelial dysfunction.

IntroductionThe rupture of an intracranial aneurysm is a neuro-logical emergency. The urgency of the situation mightnot seem intuitively obvious because many patientspresent only with a headache and initially have a nearlynormal neurological examination. In the first 24 h,rebleeding is a major risk and can lead to early morbidityor even brain death. After the aneurysm is secured (ie,excluded from the circulation), the patient enters a newphase punctuated by cerebral vasospasm and decreasedcerebral perfusion. Avoiding secondary damage thenbecomes the primary goal of care. Some patientspresent in a much worse clinical condition, requiring

complex management of pulmonary oedema, cardiacfailure, and arrhythmias. Other patients needemergency evacuation of a cerebral haematoma ordecompressive craniectomy to control mass effect.

There has been a notable change in the managementof aneurysmal subarachnoid haemorrhage (aSAH) overthe past decade. In this era of neurointervention andneurointensive care, a multidisciplinary team isrequired to respond to the needs of the patient. Mortalityfrom aSAH is decreasing1and we are making progressin the understanding of its complex pathophysiology.Furthermore, new management strategies haveemerged and their use might enable morepatients to return to a good or even a full level of

functioning.In this Review, we first provide a practical overview of

the care of patients with aSAH from the time of theirfirst hospital assessment. Second, we highlight recentdiagnostic and therapeutic advances and discusspromising new treatment options. This Review is notintended to be a guideline or to represent practicerecommendations and we do not strictly follow therules of evidence-based medicine. When evidence isavailable, we present a critical assessment of itsstrengths and weaknesses; when there is no evidenceavailable, we offer recommendations based on ourexperience.

Initial managementIn the emergency departmentThe acute physiological abnormalities caused by therupture of an intracranial aneurysm can be devastating.Probably no other acute neurological illness provokes theextent of sudden increase in intracranial pressure andsympathetic outflow as that produced by aSAH. Suddendeath occurs in 1015% of individuals at the time ofrupture.2,3 Coma from intracranial hypertension andcardiopulmonary complications caused by neuro-cardiogenic injury are common among survivors withextensive haemorrhage. Thus, the initial phase of care ofpatients with aSAH can be very challenging, yet this

period is less well studied.

Diagnosis of aSAHDiagnosis is suspected by the clinical signs and symptomsbut must be confirmed by brain imaging or CSF analysis.CT scanning has a high sensitivity for the detection ofsubarachnoid blood (>95%).4,5CT scans also offer valuableinformation to estimate the risk of delayed vasospasm; arecent modification to the classic Fisher grading score6recognises that the presence of not only cisternal but alsointraventricular blood increases the risk of vasospasmand this modified scale should preferentially be used(table 1).7,8The score described by Hijdra and colleagues9has greater predictive power than the Fisher score,10but

is less often used because it is more laborious. Only earlyCT scans should be used to estimate the risk ofvasospasm; scans that are done more than 48 h after thetime of bleeding lose predictive value.11

The most common causes for aSAH with false negativeCT scans are small haemorrhages and delayedpresentation. Clinical suspicion of aSAH with a negativeCT scan demands that a lumbar puncture is done.1214CSFshould be centrifuged and examined for xanthochromia,which can be present as early as 6 h after the haemorrhageand is uniformly evident 12 h later.15 Spectrophotometricanalysis is more sensitive than visual inspection of theCSF, but visual inspection has good specificity.16Although


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MRI is rarely used for the initial diagnosis of aSAH,haemosiderin-sensitive sequences (such as gradient echo,T2*, and susceptibility-weighted imaging) have a highsensitivity for the diagnosis of any form of intracranialhaemorrhage. In fact, MRI scans are more sensitive thanCT scans when scanning is done several days after theonset of the bleeding.17

Scoring clinical severityThe severity of neurological impairment on presentation isone of the strongest predictors of outcome. As the Huntand Hess score18relies on some subjective information, wefavour the simplicity and objectivity of the World Federationof Neurological Surgeons scoring system (table 2).19

In the intensive care unit

After ensuring adequate ventilation, oxygenation, andcirculation, initial care should be focused on recognisingearly complications and preventing rebleeding. Patientsshould be referred to high-volume centres withcontinuous availability of a multidisciplinary team(including cerebrovascular neurosurgeons, endovascularspecialists, neurointensivists, brain rehabilitationphysicians, dedicated physical, occupational, and speechtherapists, and nurses with expertise in SAH) andadmitted to the intensive care unit, ideally one specialisedin neurosciences.2022

The most common cerebral complications onpresentation are acute hydrocephalus and global brainoedema. Acute hydrocephalus responds rapidly to

ventricular drainage and the resulting clinical improvementcan be dramatic.23 Global brain oedema visible on CTscans is a marker of poor prognosis and treatment is oftenineffective in these cases.24Nonetheless, as some patientswith poor clinical grade and extensive aSAH at presentationwho improve after aggressive initial resuscitation(endotracheal intubation, stabilisation of cardiopulmonaryfunction, ventriculostomy when indicated, occasionallyosmotherapy) can achieve a favourable outcome,25discontinuation of intensive care and life-support measuresduring the first 1224 h is not advisable.

Important aspects of early medical care in aSAH includeanalgesia, antiemesis, fluid administration, blood pressurecontrol, and general preventive measures (eg, stool

softeners to avoid straining, H2 receptor blockers orproton-pump inhibitors for prophylaxis of gastroduodenalulcers, and intermittent pneumatic compression of thelegs to minimise the risk of deep vein thrombosis).Analgesia can be achieved with paracetamol, tramadol, ornarcotics. Hypotonic solutions should be avoided in fluidprescription. Severe hypertension should be treated, butthere is little evidence to guide the criteria to initiateantihypertensive treatment. On the basis of indirectevidence from retrospective data, systolic blood pressuregreater than 160 mm Hg might be associated withincreased risk of rebleeding.26Hence, this cutoff point isoften used to initiate treatment with intravenous boluses

of labetalol or nicardipine infusion. However, it is prudentto avoid sudden drops in perfusion pressure because this

could cause ischaemia, particularly in patients withincreased intracranial pressure.

Calcium channel blockersNimodipine (60 mg every 4 h for 21 days by enteral route)is started on admission to the intensive care unit. Theuse of this calcium channel blocker to decrease the riskof delayed ischaemic damage and poor functionaloutcome is supported by level I evidence (ie, fromrandomised controlled trials).27Of note, oral nimodipinedoes not decrease angiographic vasospasm and its benefithas been attributed to neuroprotection. In trials that havetested calcium antagonists with more potent vasodilatoryeffects (eg, intravenous nicardipine), these drugs reduced

angiographic vasospasm but did not prevent delayedischaemia; falls in arterial blood pressure that inducedcerebral hypoperfusion might have given rise to thenegative results in these studies. Thus, when usingnimodipine, it is important to ensure that systemic bloodpressure is not compromised. If nimodipine causeshypotension, the dose of the medication can be halvedand given every 2 h.

AnticonvulsantsWe do not recommend the use of prophylacticanticonvulsants. Phenytoin has been associated withpoor outcome in aSAH.28The reasons for this detrimental

Fisher scale Modified Fisher scale

0 No SAH or IVH

1 No SAH or IVH Minimum or thin SAH, no IVH in either lateral ventricle

2 Diffuse, thin SAH, no clot >1 mm in

thickness

Minimum or thin SAH with IVH in both lateral

ventricles

3 Localised thick layer of subarachnoid clot>1 mm in thickness

Thick SAH, no IVH in either lateral ventricle

4 Predominant IVH or intracerebral

haemorrhage without thick SAH

Thick SAH with IVH in both lateral ventricles

The modified Fisher scale incorporates the effect of IVH on the risk of vasospasm and delayed ischaemic damage.

Delayed cerebral ischaemia can be predicted by the appearance of the initial CT scan of the brain. SAH=subarachnoid

haemorrhage. IVH=intraventricular haemorrhage.

Table :Comparison of the traditional Fisher radiological grading scale and a proposed modified

grading scale

Hunt and Hess grading system WFNS grading systemI Asymptomatic or mild headache GCS sum score 15 without hemiparesis

II Moderate to severe headache, nuchal rigidity, nofocal deficits other than cranial nerve palsy

GCS sum score 1413 without hemiparesis

III Confusion, lethargy, or mild focal deficits other

than cranial nerve palsy

GCS sum score 1413 with hemiparesis

IV Stupor or moderate to severe hemiparesis GCS sum score 127 with or without hemiparesis

V Coma, extensor posturing, moribund appearance GCS sum score 63 with or without hemiparesis

WFNS=World Federation of Neurological Surgeons. GCS=Glasgow coma scale.

Table :Clinical grading scales for patients presenting with aneurysmal subarachnoid haemorrhage


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effect are not known, but an interaction with nimodipinehas been proposed.29Anticonvulsants should be reservedfor patients with documented clinical or electrographicseizures. In these cases, selection of a differentantiepileptic drug from phenytoin is reasonable. Incomatose patients with poor-grade aSAH, it might bereasonable to obtain an electroencephalogram (EEG) toassess for non-convulsive status epilepticus.30 However,these subclinical seizures are often refractory toantiepileptic therapy and unfavourable prognosis mightnot be altered by attempts to control them.30,31

Preventing rebleedingRebleeding, previously the main cause of death among

hospitalised patients with aSAH, has become lessfrequent because of the widespread practice of treatingthe ruptured aneurysm as early as possible. Aneurysmsare most often secured within 24 h of hospitalisation, andtreatment of the aneurysm should always be attemptedbefore the fourth day, when the risk of delayed vasospasmbegins to increase. Antifibrinolytic drugs (eg, amino-caproic acid and tranexamic acid) can prevent rebleedingbut they increase the risk of cerebral infarction with nonet benefit in the overall functional outcome.21,32 Theiruse should be reserved for carefully selected cases (eg,patients with particularly high risk of rebleeding in whomthe intervention to secure the aneurysm must bepostponed). Short-term (


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Age remains an important consideration when decidingthe treatment technique to secure the aneurysm.Endovascular coiling was associated with better functionaloutcome than neurosurgical clipping in a subgroup ofelderly patients (>65 years of age) in ISAT who presentedwith good clinical grade and SAH from small rupturedaneurysms in the internal carotid artery or posteriorcommunicating artery. Conversely, patients with middlecerebral artery aneurysms had better outcomes withneurosurgical clipping than with endovascular treatment.Clinical results were similar with both techniques whenthe ruptured aneurysm was located in the anteriorcommunicating or anterior cerebral artery region.45Meanwhile, some have argued that the advantage ofendovascular coiling over surgical clipping cannot beassumed for patients younger than 40 years of age. The

reasoning behind this argument is that younger patientscan tolerate surgery better than older individuals, andtherefore they are more likely to benefit from the betterlong-term protection given by clipping.46

Management of patients with poor clinical gradeManagement of poor-grade patients is particularlychallenging because these patients are most oftenintubated and sedated. Thus, physical examinationcannot be reliably used to recognise signs of delayedischaemia. Invasive and non-invasive brain monitoringtechniques can be used for these patients. Measurementsand techniques include venous oximetry (by jugular bulbcatheters), brain tissue oxygen tension (by probes such

as the Licox catheter, GMS, Kiel-Mielkendorf, Germany),cerebral microdialysis, continuous EEG, and continuoustranscranial doppler, as well as measurements of cerebralperfusion pressure and intracranial pressure.4749 Theresults from these techniques are best interpreted whencombined in protocols of multimodality brainmonitoring.Although these techniques provide a wealthof physiological information and can be used to identifypatients with worsening brain injury, whether their usein guiding the management of patients with poor-gradeaSAH leads to improved functional outcomes remainsto be proven.

In patients with raised intracranial pressure, osmoticdrugs are the first line of therapy. We favour hypertonic

saline in patients with vasospasm because it can improvecardiac output and does not produce as much osmoticdiuresis as mannitol.50 Induction of therapeutichypothermia is practised in some cases, but systemiccomplications are common when patients must be kepthypothermic for several days.51 Decompressivecraniectomy might be useful in cases of recalcitrantintracranial hypertension. The ideal timing is unknown,but we believe that decompressive craniectomy should bepursued without delay when medical treatment is deemedineffective. If intracranial hypertension has producedsecondary ischaemic injury, craniectomy might enablesurvival but with very limited functional recovery.52

Vasospasm and systemic complicationsDiagnosis of vasospasmThe risk of vasospasm increases between 3 and 7 daysafter aSAH, although earlier vasospasm can occur andmight be associated with poor outcome.6Fewer than 4%of deficits occur after day 13. More than 60% of patientswith aSAH develop cerebral vasospasm during thehospital course, but only about 30% will becomesymptomatic. Cerebral vasospasm tends to be moresevere in younger patients with poor neurological grade,thick subarachnoid clot, intraventricular haemorrhage,and history of smoking.7,53 The onset of symptomaticvasospasm can be sudden or gradual and insidious.Headache and increasing neck stiffness are non-specificsigns. Patients will commonly present with increasingconfusion, delirium, or decreased consciousness, with or

without focal deficits. Techniques available for monitoringvasospasm and cerebral perfusion are listed in table 3.Transcranial doppler ultrasonography is a widely

accepted method for screening and monitoring ofvasospasm.54However, transcranial doppler has inherentlimitations: it is operator dependent and does not provideuseful information in patients with poor temporalultrasonographic windows (a problem often encounteredin older women). The sensitivity and specificity oftranscranial doppler for the diagnosis of symptomaticvasospasm and subsequent cerebral infarction on CT scansrange from 70% to 80%.5557Transcranial doppler resultscorrelate adequately with findings on digital substractionangiography when vessels can be well insonated.58 The

sensitivity differs depending on the vessel involved; it ishighest for the middle cerebral artery but lower forintracranial internal carotid and anterior cerebral arteries.In one study, the negative predictive value for middlecerebral artery velocities of less than 120 cm/s was 94%and the positive predictive value for middle cerebral arteryvelocities greater than 200 cm/s was 87% for transcranialdoppler monitoring compared with digital substractionangiography, the gold standard method for the diagnosticassessment of cerebral vasospasm.59An increase in meanflow velocity of more than 50 cm/s over 24 h is also areliable marker of vasospasm.60Use of the intracranial toextracranial vessel mean flow velocity ratio (known as theLindegaard ratio) helps to discriminate between vasospasm

and hyperaemia; velocities three times higher in themiddle cerebral artery than in the extracranial internalcarotid artery are indicative of angiographic vasospasm,and a ratio of six indicates severe angiographic vasospasm.61A lower threshold velocity has been recommended for theultrasonographic definition of basilar artery vasospasmmonitoring (85 cm/s)62and values greater than 115 cm/sreliably identified patients at risk of brainstem ischaemiaas detected by single photon emission computedtomography.63A basilar to vertebral artery ratio of greaterthan three with mean velocities faster than 85 cm/s mightfurther increase the diagnostic accuracy of transcranialdoppler for the detection of basilar artery vasospasm.64


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The major advantages of digital substraction angiographyare high accuracy and ability to undertake endovasculartreatment of existing vasospasm immediately. However,this technique is an invasive procedure that requires thepresence of a qualified neurointerventionalist, oftendemands general anaesthesia, and is associated with smallrisks of contrast nephropathy and stroke. Additionally,digital substraction angiography might not identifyvasospasm in up to a quarter of patients with aSAH whodevelop radiological infarctions.55

CT angiography has a good correlation with digitalsubstraction angiography for the identification ofvasospasm in proximal arterial segments.65 Agreementbetween CT angiography and conventional angiographyis close to 90% in cases of severe vasospasm, withexcellent agreement among different observers.66Discrepancies between the two tests are more commonwhen vasospasm is mild or moderate.65 When CTangiography is used to study vasospasm, the axial sourceand three-dimensional images must be examined forsymmetry and calibre of the cerebral vessels. Having abaseline CT angiography at presentation is useful to beable to assess interval changes in vessel diameter. Metal

artifacts from clips or coils often diminish the quality ofthe images.

CT perfusion is being increasingly used for thediagnosis of vasospasm. Good correlation with digitalsubstraction angiography has been reported. Absolutecerebral blood flow values of less than 25 mL/100 g/minand mean transit times greater than 65 s are associatedwith severe vasospasm and high risk of delayed ischaemicdeficits.67A mean transit time with a threshold of 64 swas the most sensitive parameter for the diagnosis ofcerebral vasospasm (as confirmed by angiogram), with anegative predictive value of 987%.68CT perfusion and CTangiography had a higher positive predictive value thantranscranial doppler in this study.69 Other investigatorshave identified delayed time to peak as the most reliablepredictor of delayed cerebral ischaemia.70 In practice,

visual inspection of CT perfusion maps can be reliablyused to evaluate hypoperfusion (figure 2).71CT perfusionmaps can show decreased perfusion in areas with mild orno macrovascular vasospasm on CT angiography, thusenabling recognition of ischaemic risk that wouldotherwise remain unnoticed.72,73 In fact, findings on CTperfusion studies have better predictive values than thoseof CT angiography for the diagnosis of delayed cerebralischaemia in patients who have clinical signs ofdeterioration. 74Radiation exposure is a disadvantage thatlimits the suitability of CT perfusion as a serial test.

MRI, particularly diffusion-weighted imaging, hasgreater sensitivity than does CT for the diagnosis of acuteischaemia related to vasospasm.7578 Perfusion-weighted

imaging might also provide useful information (figure 3).Abnormal perfusion-weighted imaging might be used topredict neurological deficits with greater sensitivity thantranscranial doppler.79 As with CT perfusion, perfusion-weighted MRI can be used to identify hypoperfusion interritories not affected by substantial angiographicvasospasm (most often the basal ganglia and watershedregions).80Mismatch between perfusion-weighted imagingand diffusion-weighted imaging can be used to identifyischaemic penumbra in patients with vasospasm.81

Testing of vasomotor reactivity by use of transcranialdoppler with CO2challenge can be done at the bedside.This method was a very sensitive early predictor ofvasospasm in a recent small series.82Monitoring regional

and local oxygenation with jugular bulb catheters andbrain probes (such as the Licox catheter) remainsconfined to some specialised centres.48Whether decreasesin the oxygen concentration in brain tissue indicate a riskof ischaemia or a very early marker of establishedischaemic damage is unclear. Other methods to monitorregional brain perfusion, such as thermal diffusionintracerebral microprobes, are still mostly experimental.

Treatment of vasospasmInitial evaluation should involve assessment of volumestatus. It is important to ensure that the patient does notbecome volume depleted, sometimes a challenging task

Advantages Disadvantages

Catheter

angiography

Most sensitive for large-vessel spasm

Enables measurement of cerebral circulation timeCan be combined with intra-arterial treatment

Invasive

Labour intensiveCannot be repeated too oftenIodine use

Radiation exposure

Need for transportation

Transcranialdoppler

Non-invasiveDone at bedside

Can be done daily to follow trends*

Good correlation with catheter angiographyCan be combined with CO2challenge to test VMR

Depends on presence of bone windows

Operator-dependentDoes not assess the microcirculation

well

CTangiography

Non-invasiveCan be combined with CT perfusion

Good correlation with catheter angiography

Cannot be repeated too oftenIodine use

Radiation exposureNeed for transportation

CT perfusion Evaluates actual cerebral perfusionQuantifiable measures

Can detect ischaemia even without detected

angiographic vasospasm

Cannot be repeated too oftenIodine use

Radiation exposure


Magneticresonance

angiography

Non-invasiveCan be combined with DWI/PWI

Cannot be repeated too oftenNeed for transportation

MRI with DWI/

PWI

Measures actual cerebral perfusion

Easy identification of ischaemic penumbra

Cannot be repeated too often


Single photonemission

computed

tomography

Measures cerebral perfusion Cannot be combined with vesselimaging in the same session

Radioactive exposure


Jugularoximetry

Regional measure of brain oxygenationCan be measured frequently

InvasiveSusceptible to artifact

Brain tissue O2 Local measure of brain oxygenationContinuous measure

InvasiveVery limited spatial resolution

VMR=vasomotor reactivity. DWI=diffusion-weighted imaging. PWI=perfusion-weighted imaging. *Continuous

transcranial doppler monitoring is also possible.

Table :Most commonly used techniques to diagnose and monitor vasospasm and cerebral ischaemia


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in patients with excessive natriuresis. The ideal protocolfor salt and volume replacement has not been established.We prefer 09% saline solution in patients with normalserum sodium concentrations and 15% sodium chloridein patients who develop hyponatraemia, which can begiven via peripheral veins. Other concentrations of salinesolution (3%, 75%) have been used, as well as colloidsolutions (most commonly albumin in 5% and 25%solution). Supplemental 5% albumin solution limits lossof fluid and sodium by decreasing glomerular filtrationrate, which leads to a decrease in the total amount offluids required to maintain an adequate volume status.83However, there is no evidence to support the routine useof colloid solutions in aSAH, and crystalloid solutionsshould be standard fluid therapy.

The main goal of fluid management in patients without

clinical vasospasm is to maintain neutral fluid balancetaking into account insensible losses (eg, fluid lost byevaporation of sweat). Some protocols require invasivecentral venous pressure monitoring with a recommendedpressure of between 6 mm Hg and 8 mm Hg and apulmonary capillary wedge pressure of between 8 mm Hgand 12 mm Hg. However, non-invasive methods tomonitor intravascular fluid status are becoming availableand might be preferable.84 Prophylactic hypervolaemia isnot recommended; this strategy did not improve cerebralblood flow or prevent symptomatic vasospasm or delayedischaemic damage in a randomised controlled study,85andit can be associated with increased risk of cardiopulmonarycomplications owing to fluid overload.

Since its description,86

haemodynamic augmentationtherapy has become the mainstay of medical treatmentof cerebral vasospasm in patients with aSAH.87 Theobjective of haemodynamic augmentation is to improvecerebral perfusion by overcoming the increased vascularresistance imposed by vasospasm. Although the effi cacyof this treatment has not been tested in randomisedcontrolled trials,88 the benefits of implementing suchaugmentation are supported by lower levels of evidence89,90and can be seen in practice.

Haemodynamic augmentation is also traditionallyknown as triple H therapy for its components:hypervolaemia, hypertension, and haemodilution.However, there is substantial controversy with regard to

the relative value of these components. Induction ofhaemodilution is now used less often because theimprovements in cerebral blood flow related to diminishedblood viscosity do not produce a net benefit if the fall inhaematocrit compromises oxygen delivery to the brain.91Meanwhile, more recent studies have questioned theusefulness of hypervolaemia.92,93 In one study,93 inducedhypertension improved regional cerebral blood flow andbrain tissue oxygenation, but these benefits disappearedafter induction of hypervolaemia. Other investigatorsfound induced hypertension to be more effective and saferthan hypervolaemia in achieving improved brainoxygenation.92Nonetheless, there are data that lend support

to the usefulness of hypervolaemia. Saline boluses(15 mL/kg over 1 h) increased regional cerebral blood flowas measured by PET scans in brain regions most vulnerable

to ischaemia.94

The value of induction of hypervolaemiamight depend on the baseline volume status of the patient.Administration of fluids might benefit truly euvolaemicpatients, but not those who are already volume expandedbefore the diagnosis of symptomatic vasospasm. In fact,attempts to produce increased hypervolaemia in patientswith volume expansion might provoke complications fromfluid overload.

Several vasopressors can be used to inducehypertension, including phenylephrine, norepinephrine,and dopamine. Vasopressin is an effective vasopressor,but is not commonly used in patients with aSAH becauseof its potential to exacerbate hyponatraemia. Meanwhile,

Figure :CT perfusion for the diagnosis of delayed ischaemia after aneurysmal subarachnoid haemorrhage

Large area of hypoperfusion in the territory of the right middle cerebral artery revealed by prolongation of mean

transit time on CT perfusion obtained 6 days after aneurysm rupture (A, arrows). The only abnormality onneurological examination at the time of this scan was left-sided extinction to double simultaneous tactile

stimulation. Cerebral angiography confirmed the presence of severe spasm affecting the M1 segment of the right

middle cerebral artery (B, arrow). The patient was successfully treated with balloon angioplasty.

Figure :Perfusion-weighted imaging and diffusion-weighted imaging for the diagnosis of delayed

ischaemia after aneurysmal subarachnoid haemorrhage

Presence of ischaemic penumbra in a patient with documented delayed vasospasm 9 days after onset of aneurysmal

subarachnoid haemorrhage. Note the mismatch between the more extensive areas of decreased perfusion on

perfusion-weighted imaging (A, arrows) and the smaller regions of restricted diffusion on diffusion-weighted

imaging (B, arrows).

BA

BA


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augmentation of cardiac output with inotropics (eg,dobutamine and milrinone) is preferred in some centresand data are available to support this strategy.95

About 1020% of patients treated with haemodynamicaugmentation have complications, mostly pulmonaryoedema and, much less commonly, myocardialischaemia and cardiac arrhythmias.96,97 Increasedcerebral oedema, posterior reversible encephalopathysyndrome, and haemorrhagic conversion of ischaemicstroke are complications rarely seen in practice.90Endovascular therapy should be pursued when signs ofclinically significant fluid overload become evident.Cardiopulmonary complications that demand acute,aggressive treatment with diuretics and vasodilatorsmust be avoided as those interventions almostinvariably lead to cerebral ischaemia in patients with

active vasospasm.

Endovascular therapies for vasospasm includetransluminal balloon angioplasty and super-selectiveintra-arterial infusion of vasodilators.98,99 Although notproven effective in randomised controlled studies, theseinterventions are reasonable options in patients who arerefractory to medical therapy or when haemodynamicaugmentation is considered unsafe owing to poorcardiovascular reserve. Angioplasty is highly effective inrelieving focal vasospasm that involves the proximalsegments of the major intracranial vessels at the level ofthe circle of Willis.99Early treatment seems to maximisethe chances of averting ischaemia from severevasospasm.100The effects of angioplasty are durable andthe procedure is relatively safe when done by experiencedneurointerventionalists (although arterial wall rupture,dissection, local thrombosis, and reperfusion injury are

possible). Intra-arterial vasodilators can ameliorate distaland diffuse vasospasm, but their effects are transient.Papaverine was the first drug used for this indication;however, this drug is neurotoxic and can increaseintracranial pressure and also provoke seizures, transientcortical blindness, and irreversible brain injury.101Nimodipine,102 nicardipine,103,104 and verapamil105 havesince emerged as safer alternatives.

Treatment of medical complicationsThe presentation and course of aSAH can be associatedwith several neurological and systemic complications.14Panel 1 summarises our practical recommendations forthe management of aSAH, including measures to prevent

and treat the most common complications.Fever106 and hyperglycaemia107109 are associated withworse outcome in aSAH. The detrimental effects of thesephysiological alterations in aSAH seem to be at leastpartly independent of the presence of vasospasm.106,109Nonetheless, fever and hyperglycaemia have beenassociated with symptomatic vasospasm110112 and couldexacerbate ischaemic neuronal damage in these patients.The value of intensive treatments to maintainnormothermia and normoglycaemia needs to be formallystudied.

Neurogenic pulmonary oedema tends to occur earlyafter aneurysm rupture.113This oedema is thought to becaused by the sudden increase in sympathetic activation,

leading to increased hydrostatic pressure (whichprobably accounts for most cases) or increased alveolarpermeability.114Although the oedema might be massiveinitially, it responds well to ventilatory support with ahigh level of positive end-expiratory pressure.Neurogenic pulmonary oedema is more common inpatients with poor clinical grades, and patients with thiscomplication might be more prone to vasospasm,although this association might not be independent butinstead associated with the severity of the SAH. Thedifferential diagnoses include cardiogenic pulmonaryoedema and pneumonia (related to aspiration ormechanical ventilation).115

Panel :Our guiding principles for the management of aneurysmal subarachnoid

haemorrhage

Recommendations:

Admit patient to an intensive care unit with specialised nursing care

Be part a multidisciplinary team

Assess patient for cardiopulmonary neurogenic injury

Optimise oxygenation

Treat hydrocephalus promptly and aggressively

Order nimodipine

Secure the aneurysm as soon as possible

Pursue endovascular occlusion if feasible

Consider early surgical decompression if raised intracranial pressure

Maintain euvolaemia*

Do neurological examinations very frequently

Monitor brain perfusion, not just vessel diameter

Augment blood pressure if hypoperfusion is present

Pursue angioplasty or intra-arterial drugs if hypoperfusion is refractory

Keep patients body temperature normal

Maintain blood sugar concentrations, ideally between 80 and 150 mg/dL

Monitor serum sodium concentrations and use hypertonic intravenous fluids if

hyponatraemia is present

Use preventive measures against deep vein thrombosis

Cautions:

Do not give up on poor-grade patients

Do not minimise the importance of sleepiness

Do not use frequent or large doses of sedatives or narcotics Do not order fluid restriction

Do not infuse hypotonic intravenous solutions

Do not induce prophylactic hypervolaemia

Do not overload patients with fluids, even if they have vasospasm

Do not reduce blood pressure after aneurysm treatment

Do not prescribe phenytoin

Do not give glucocorticosteroids regularly

Do not rely on a single monitoring modality for vasospasm or hypoperfusion

Do not accept neurological deficits and functional impairment as unavoidable

*Mild hypervolaemia is reasonable in patients with symptomatic vasospasm. Not to be confused with free water restriction,

which is appropriate in hyponatraemic patients.


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Neurocardiogenic injury can be provoked by excessivesympathetic stimulation. The resulting cardiomyopathyis known as apical ballooning syndrome or takotsubocardiomyopathy because of the echocardiographicappearance.116118 Takotsubo syndrome is also morecommon in patients with poor clinical grade atpresentation. Typically, the disorder manifests over thefirst 48 h with signs of left ventricular dysfunction andreverses spontaneously over the subsequent 23 weeks.There might also be a slight increase in cardiac enzymesin the serum,119but prominent increases in these chemicalmarkers or major ischaemic changes in the electro-cardiogram should raise suspicion of myocardialischaemia.120

Hyponatraemia after aSAH, although frequentlyobserved, is most often asymptomatic. However, very low

(eg,


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affects the endothelial function and microcirculation.133Robust theoretical rationale and strong experimental datahave led to the design of clinical trials that investigatenovel therapies for vasospasm and protection againstdelayed ischaemic damage. Panel 2 summarises thecurrent state of the evidence for various therapeuticoptions tested for this indication in clinical trials.

StatinsIndependent of their effects on reducing cholesterol,statins also have pleiotropic effects that includeamelioration of glutamate-mediated excitotoxicity,attenuated production of reactive oxygen species, up-regulation of endothelial nitric oxide synthase, anddiminished inflammatory reaction by modulation of thecytokine response.154,155 In two small randomised trials,

statin treatment provided benefit across various endpoints,including ultrasonographically defined vasospasm,156,157duration of impaired autoregulation,157 vasospasm-relateddelayed ischaemic deficits,157improved functional, physical,and psychosocial outcome at 6 months,158and reduction inall-cause mortality.158Statin therapy was safe in both thesesmall trials; specifically, there were no severe cases ofmyositis or hepatitis reported.156,157 The favourable resultsobserved in one of these trials might be partly explained bythe poor outcomes seen in the placebo group.158

However, the results of studies that have investigatedstatins in SAH have not been consistently favourable.

Data from two other small, randomised controlled studiesindicated no differences in the rate of vasospasm-relatedinfarcts or functional outcomes between statin-treatedpatients and controls.159,160 In fact, the most recent meta-analysis of available randomised studies concluded thatthere is no evidence to support a beneficial effect of statinsin SAH.161 Furthermore, after the first reports indicatingbeneficial effects of statin use on vasospasm, centres thatmodified their practice and began giving statin therapy toall their patients with SAH have subsequently reported noimproved outcomes among statin-treated patientscompared with historical controls treated at the sameinstitutions.162164Therefore, although preliminary data onthe use of statins for the prevention of severe vasospasmseem encouraging, early promising results must beconfirmed in larger, multicentre trials before statins can

be recommended for this indication (table 4).165

One suchtrial (the STASH [Simvastatin in Aneurysmal SubarachnoidHaemorrhage] trial) is currently underway.148

Endothelin antagonistsEndothelin-1 is the most potent physiological vaso-constrictor, and increased activity of endothelin-1 seemsto play a major part in the pathogenesis of cerebralvasospasm.166This vasoconstrictor is postulated to workthrough nuclear signal transduction pathways.167 Therehas been substantial interest in the development ofendothelin-1 receptor antagonists for the treatment ofcerebral vasospasm,168particularly in drugs that block theactivation of endothelin-1A receptors as they have been

specifically implicated as mediators of cerebral vesselconstriction.169After encouraging results from a phase 2a study, 170

data from a double-blind trial (the CONSCIOUS-1[Clazosentan to Overcome Neurological Ischemia andInfarction Occurring After Subarachnoid Hemorrhage]trial) indicated that intravenous clazosentan, anendothelin-1 receptor antagonist, reduced moderate orsevere angiographic vasospasm in a dose-dependentmanner (66% for the high dose vs 23% for placebo inthe intention-to-treat analysis), but did not improveclinical outcomes.171 In a post-hoc analysis that used astricter definition for vasospasm-related infarctions andcentral adjudication of endpoints, clazosentan was

associated with a trend towards better clinicaloutcomes.171 However, as results for clinical outcomeswere positive only after the substantial modificationsimplemented in the post-hoc analysis, the strength ofthese conclusions is diminished.

Systemic hypotension, anaemia, pulmonarycomplications (probably related to fluid retention), anddeath were more common in the treatment arms than inthe placebo group. However, most fatalities were caused byintraoperative complications; hence, they were not thoughtto be related to the drug under investigation. Thediscrepancy between angiographic and clinical outcomesmight be explained by systemic complications or the

Statin type

and dose

Population

size

Main results

Randomised,

placebo-controlledtrial157,158

Pravastatin

40 mg per day

80 Reduced vasospasm

Reduced severe vasospasmDecreased duration of impaired autoregulation

Reduced delayed ischaemic deficits related to spasm

Reduced mortalityImproved functional outcome

Randomised,

placebo-controlled

trial156

Simvastatin80 mg per day

39 Reduced symptomatic vasospasmAttenuated serum markers of brain injury

Randomised,

placebo-controlledtrial159

Simvastatin

80 mg per day

39 No difference in vasospasm, delayed cerebral

infarctions, or functional outcome

Randomised,

placebo-controlled

trial160

Simvastatin

80 mg per day



Better lipid panel but no difference in other laboratory

markersObservational,

historical control

trial163

Simvastatin

80 mg per day



Observational,historical control

trial164

Simvastatin80 mg per day

340 No difference in symptomatic spasm, functionaloutcome, in-hospital mortality, or length of hospital

stay

Observational,

historical control

trial162

Simvastatin

40 mg per day

130 No difference in vasospasm, symptomatic spasm, or

functional outcome and mortality at discharge

Modified from Rabinstein,165with permission from Springer.

Table :Prospective comparative clinical studies that have investigated statins for the treatment of

aneurysmal subarachnoid haemorrhage


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possibility that other mechanisms in addition to vasospasmcould substantially affect prognosis in these patients.133Two more studies (CONSCIOUS-2 and CONSCIOUS-3 inclipped and coiled patients, respectively) investigating thisendothelin antagonist are in progress.146,147

Magnesium sulfateHypomagnesia occurs in about half the patients withSAH and its presence is correlated with a high risk ofdelayed ischaemic deficits and a poor 3-month outcome.172Magnesium antagonises voltage-gated calcium channelsand has cerebral vasodilator properties.173 Data fromanimal studies indicate that magnesium might beneuroprotective and might reverse cerebral vasospasmand decrease delayed ischaemic deficits.174

Results from pilot studies have established the

feasibility of magnesium sulfate infusion for patientswith SAH.175,176Subsequently, the MASH (Magnesium inAneurysmal Subarachnoid Hemorrhage) Study Groupreported the results of a randomised controlled study of283 patients with aSAH, in which a continuous infusionof magnesium sulfate (64 mmol/L per day) was startedwithin 4 days of aneurysm rupture and continued untilday 14 after occlusion of the aneurysm. This treatmentwas associated with a 34% reduction in the risk of delayedcerebral ischaemia (hazard ratio 066; 95% CI 038114)and a risk reduction in poor functional outcome at3 months of 23% (risk ratio 077; 054109). However,confidence intervals were wide and included 10 for bothendpoints.177Data from another placebo-controlled study

indicated a lower incidence of symptomatic vasospasmin patients receiving magnesium infusion (23%) versusthat noted in the placebo group (43%), but withoutdifferences in functional outcome. The high rate ofsymptomatic vasospasm in the placebo arm of this studycould have affected the comparison in favour of themagnesium group.178 In randomised studies that havecompared magnesium sulfate infusion versus intra-venous nimodipine, similar outcomes in both groupswere reported.179,180Although magnesium infusion seemsto be safe, it can induce hypotension, hypocalcaemia, andbradycardia.181

Meta-analyses of available studies indicate thatmagnesium sulfate infusion might be beneficial.21,182However, trials done so far have not had adequatestatistical power owing to their small size, and thedifferent designs limits the validity of a pooled analysis oftheir results (table 5). Hence, at present, the evidence isinsuffi cient and larger randomised controlled trials, suchas the ongoing MASH-II trial,149are needed to determinethe safety and effi cacy of magnesium sulfate infusionbefore it can be recommended for patients with aSAH.

Other investigational therapiesMicrothrombosis183 and microembolism184 can occur inaSAH. However, data from trials that have investigatedantiplatelet drugs showed no conclusive benefit.139Enoxaparin did not prevent ischaemia and was associated

with an increased rate of additional intracranialbleeding.132

Impaired cerebrovascular relaxation related to damagein the nitric oxide system has been implicated in thepathogenesis of cerebral vasospasm.185,186 Preliminaryevidence has suggested that nitric oxide donors, such asintraventricular sodium nitroprusside, might amelioratecerebral vasospasm.187,188 This treatment strategy hasstrong theoretical and experimental rationale and furtherinvestigations are warranted.

Albumin was traditionally used in aSAH to promotevolume expansion and haemodilution. However, albuminmight also be protective against cerebral ischaemia.189Inone retrospective analysis,190the incidence of vasospasm

was similar in groups treated with and without albumin,but there was a trend towards better 3-month outcomesin patients who received albumin. A multicentre trial(the ALISAH [Treatment of Subarachnoid Hemorrhagewith Human Albumin] study) to test different doses ofalbumin infusion is underway.151

A multicentre study tested the value of prophylacticangioplasty of major intracranial vessels in patients withhigh risk of vasospasm (Fisher grade 3). 144Patients treatedwith prophylactic angioplasty had a slight reduction inthe incidence of delayed ischaemic neurological deficits(235%) compared with the standard care group (318%),

Magnesium infusion Population

size

Main results

Randomised, single-blind,placebo-controlled trial176

To maintain serum concentrations455 mg/dL for 10 days

40 No difference in symptomatic spasm or functional outcome

Randomised, double-blind,placebo-controlled trial177

64 mmol/L per day until day 14 283 Reduction in delayed cerebral infarctions and poor outcome (butwide CIs including 10)

Randomised, double-blind,

placebo-controlled trial17820 mmol bolus, then 80 mmol per day

until day 14

60 Reduct ion in symptomatic vaso spasm

No difference in functional outcome

Randomised versus intravenous

nimodipine trial17904 mmol/kg bolus, then 12 mmol/kg

daily for 721 days

104 No differences between the groups

Randomised, single-blind,

placebo-controlled trial181Adjusted to maintain serum

concentration of twice the baselineuntil day 12

58 No differences in delayed ischaemia or functional outcomeHigher rates of hypotension and hypocalcaemia

MgSO4infusion stopped in 52% of patients owing to side-effects

Table :Prospective randomised clinical studies that have investigated magnesium infusion for the treatment of aneurysmal subarachnoid haemorrhage


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Review

but no benefit in functional outcome at 3 months.Although overall mortality was similar in both groups(21% with prophylactic angioplasty vs188% in controls),three patients died of vessel rupture from prophylacticangioplasty. Unless further research that is focused on

well selected patients can indicate unquestionablebenefits on functional outcome, prophylactic angioplastycannot be recommended because of its invasiveness andinherent risk of vessel rupture.

In a non-randomised, single-centre study, lumbardrainage was associated with substantially lower rates ofsymptomatic vasospasm and vasospasm-related cerebralinfarction compared with no CSF drainage.191 However,these findings need to be replicated. Lumbar drains aresafe in selected patients with aSAH,192but this still needs tobe tested in larger populations. Enhancing cisternal bloodclearance by simultaneous lumboperitoneal lavage andlow frequency head shaking193 or intra-cisternalfibrinolysis194,195have been suggested as alternative therapy

options, although the usefulness of these techniquesremains unproven.

Conclusions and future directionsThe care of patients with aSAH is undergoing changesthat hold great promise for improving patient outcomes.Over the past few years, we have learned about the valueof endovascular coil occlusion and embraced its use,enhanced our understanding of the mechanisms leadingto secondary brain ischaemia, and found new ways toidentify brain tissue at risk of ischaemic damage throughperfusion scans. We are now learning how to optimisethe use of these new diagnostic modalities and how toevaluate new therapeutic strategies developed from

strong theoretical rationale and experimental data. Weare abandoning old concepts that defined vasospasm andpredicted delayed ischaemia solely on the basis of thecalibre of major intracranial arteries and are focusing onthe evaluation of cerebral perfusion and the correction ofthe endothelial dysfunction that causes microcirculatoryfailure.

Nevertheless, there is still much more to learn. Forexample, we need to determine the mechanisms of acutebrain damage at the time of the bleeding and the earlyevents that trigger delayed vasospasm. We have to definethe optimum blood pressure that we should target beforethe ruptured aneurysm is secured. We need more data

on the rates of complete aneurysm occlusion with newtechniques of embolisation (eg, stent-assisted coiling,bioactive coils), which can then be used as a comparisonwith upcoming modalities, such as flow diversion. Theoptimum timing of perfusion scans and the best methodfor implementation of haemodynamic augmentation inpatients with symptomatic vasospasm are yet to beestablished. Furthermore, the value of multimodal brainmonitoring needs to be determined and the most usefulmonitoring techniques in poor-grade patients need to beidentified. In patients with persistent hydrocephalus, weshould identify more reliable predictors of the need forventriculoperitoneal shunting. The results of randomisedtrials should help to determine the safety and effi cacy ofendothelin antagonists, statins, magnesium sulfate, andlumbar drainage. Randomised studies are also needed to

evaluate the risks and benefits of transfusions in anaemicpatients and to assess the best target for insulin treatmentin those with hyperglycaemia. These and other crucialquestions demand answers, and increased collaborativeresearch will be essential to acquire them.

Contributors

AAR undertook the literature search and wrote the paper. GL and EFMWhelped with the literature search and contributed additional referencesand made critical revisions to the paper.

Conflicts of interest

AAR and EFMW have no conflicts of interest. GL serves on the advisoryboard for Actelion and Edge Therapeutics and has received unrestrictededucational grants from Synthes and ev3.

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Search strategy and selection criteria

References for this Review were identified through searchesof PubMed with the search terms subarachnoid

hemorrhage, treatment, management, cerebral

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Articles were also identified through searches of the Cochrane

library and searches of the authors own files. Only papers

published in English were reviewed.


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multidisciplinary management and emerging therapeutic

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