Controversies in the management of aneurysmal subarachnoidhemorrhage*

Neeraj S. Naval, MD; Robert D. Stevens, MD; Marek A. Mirski, MD, PhD; Anish Bhardwaj, MD, FCCM

T he rupture of an intracranialaneurysm may be associatedwith an array of severe distur-bances in intracranial and sys-

temic physiology that represent a uniquechallenge to the clinician. Surgical man-agement has traditionally emphasized theprevention of renewed intracranial bleed-ing by clipping or wrapping the respon-sible aneurysm. Medical management isbased on the detection and treatment ofcerebral and extracerebral complicationsof aneurysmal subarachnoid hemorrhage(aSAH). Cerebral complications of aSAHinclude recurrent intracranial hemor-rhage, vasospasm, cerebral infarction, hy-drocephalus, cerebral edema, and intra-cranial hypertension; extracerebralcomplications include respiratory failure,derangements of water and electrolytehomeostasis, myocardial dysfunction,

sepsis, and thromboembolism. As manyof these complications are life-threaten-ing but reversible, it is widely believedthat patients with aSAH can benefit frommanagement in an intensive care setting.

Recent years have seen a considerableexpansion in the use of image-guided en-dovascular therapies for aSAH, includingcoiling of aneurysms and balloon angio-plasty or intraarterial drug delivery forcerebral vasospasm (1– 4). These ad-vances have occurred in a general settingof increasing knowledge of aSAH epide-miology, pathophysiology, diagnosis, andprevention and of significant refinementsin microsurgical technique and in medi-cal therapy. There is a widespread percep-tion that this broader understanding andexpertise is yielding benefits in the formof improved outcome after aSAH. Indeed,a progressive increase in aSAH survivalover the past three decades has been re-ported in several studies (5–7). However,evidence of a direct relationship betweenaSAH outcomes and a specific strategy orintervention is limited (2, 3, 8, 9). Inseveral key areas of management, sup-porting data are lacking or equivocal innature, generating uncertainty and con-troversy among clinicians.

This review focuses on controversiesthat are central to the acute managementof aSAH. These include surgical vs. endo-vascular aneurysm repair, the diagnosis

and management of cerebral vasospasm,neuroprotective strategies, use of anti-thrombotic agents (thrombolytic agents,heparin, and platelet inhibitors), prophy-laxis of seizures, and the approach to ce-rebral salt wasting and to cardiac dys-function after aSAH. For eachcontroversy, a critical evaluation of theavailable evidence is coupled with recom-mendations for further clinical investiga-tion. The review is selective, focusing onthe principal debates at the expense ofother equally important but arguably lesscontroversial issues (e.g., post-aSAH hy-drocephalus and ventricular drainage).

Controversy 1: Surgical vs.Endovascular Aneurysm Repair

Endovascular coiling emerged as analternative to surgery in patients withintracranial aneurysms who were deemedpoor surgical candidates due to signifi-cant neurologic injury, the presence ofsevere medical co-morbidities, or difficultsurgical access to the aneurysm (1). Morerecent work has sought to extend theindications of endovascular coiling toother patient categories. In a small ran-domized trial of 109 patients with aSAH,3- and 12-month clinical and neuropsy-chological outcomes were the same be-tween the surgical group and the endo-vascular group (10). This was followed by

*See also p. 571.From the Division of Neurosciences Critical Care,

Departments of Neurology, Anesthesiology/CriticalCare Medicine, and Neurological Surgery, Johns Hop-kins University School of Medicine, Baltimore, MD.

Supported, in part, by U.S. Public Health ServiceNational Institutes of Health NS NS046379 and by anEstablished Investigator Grant (A. Bhardwaj) from theAmerican Heart Association.

The authors have no financial interests to disclose.Copyright © 2006 by the Society of Critical Care

Medicine and Lippincott Williams & Wilkins

DOI: 10.1097/01.CCM.0000198331.45998.85

Background: The care of patients with aneurysmal subarach-noid hemorrhage has evolved significantly with the advent of newdiagnostic and therapeutic modalities. Although it is believed thatthese advances have contributed to improved outcomes, consid-erable uncertainty persists regarding key areas of management.

Objective: To review selected controversies in the manage-ment of aneurysmal subarachnoid hemorrhage, with a specialemphasis on endovascular vs. surgical techniques for securinganeurysms, the diagnosis and therapy of cerebral vasospasm,neuroprotection, antithrombotic and anticonvulsant agents, cere-bral salt wasting, and myocardial dysfunction, and to suggestvenues for further clinical investigation.

Data Source: Search of MEDLINE and Cochrane databases andmanual review of article bibliographies.

Data Synthesis and Conclusions: Many aspects of care inpatients with aneurysmal subarachnoid hemorrhage remainhighly controversial and warrant further resolution with hypoth-esis-driven clinical or translational research. It is anticipated thatthe rigorous evaluation and implementation of such data willprovide a basis for improvements in short- and long-term out-comes. (Crit Care Med 2006; 34:511–524)

KEY WORDS: aneurysm; subarachnoid; hemorrhage; vasospasm;ischemia

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the International Subarachnoid Aneu-rysm Trial (ISAT), a multiple-center, ran-domized study of endovascular coiling vs.surgical clipping conducted in 2,143 pa-tients with aSAH who were deemed suit-able for either therapy. Posterior circula-tion aneurysms accounted for only 58 of2,143 patients (as many of these patientswere not enrolled because coiling wasconsidered the preferred modality oftreatment). At 1 yr, endovascular coilingwas associated with dependency or deathin 23.5% of patients compared with30.9% in the surgical group, a relativerisk reduction of 22.6% (p � .001). Ofconcern, however, nonprocedural re-bleeding within 1 yr was higher in pa-tients randomized to endovascular treat-ment (40 recurrent aSAHs, with 22deaths) compared with patients allocatedto neurosurgical treatment (33 patientswith aSAHs, 30-day mortality in 21 pa-tients) (2, 3).

Although widely regarded as a land-mark trial, the ISAT has been criticizedwith regard to biases in patient selection,low rates of randomization of eligible pa-tients, the definition of clinical equipoise,expertise of the neurosurgeons and inter-ventionists, the failure to use an opera-tive microscope, the higher than ex-pected morbidity in the surgically treatedgroup, the absence of angiographic dataafter the initial treatment, the lack oflong-term (�1 yr) follow-up, and the ap-propriateness of the reported outcome as-sessment scale (11, 12). An expert panelsuggested that 1-yr outcome as reportedin the ISAT is not an appropriate endpoint for the comparison of therapies,given that endovascular coiling is be-lieved to carry a risk of aneurysmal re-bleeding that extends beyond 1 yr. Indefense of ISAT, its authors observed thatoutcomes of surgically treated patients inISAT were comparable with those in aprospective, multiple-center North Amer-ican trial (13). They acknowledge that therate of randomization of eligible patientswas low (22.4%); however, they point outthat this rate was comparable with otherlarge randomized trials of vascular ther-apy such as the North American Symp-tomatic Carotid Endarterectomy Trial(14) or the Asymptomatic Carotid Athero-sclerosis Study (15), studies that havesignificantly influenced the treatment ofpatients with carotid artery stenosis.

A recent report from the ISAT trialgroup provides further crucial informa-tion regarding long-term outcomes (3).Based on 3,258 patient years of follow-up

after the first year for the endovasculargroup and 3,107 patient years of fol-low-up for the neurosurgical group, witha mean follow-up of 4 yrs, risk of recur-rent aSAH was higher in patients ran-domized to coiling (seven patients) com-pared with clipping (two patients), butmortality related to recurrent aSAH wasequal in both groups. A higher risk forseizures and poor cognitive outcomeswas seen in the surgical group, and cu-mulative 7-yr mortality curves showedmore deaths in the surgical group com-pared with coiling. The increased risk ofre-bleeding in the coiling group did notseem to reverse the early benefit seenwith this modality. Notwithstanding itslimitations, ISAT represents level I evi-dence that in this patient population, en-dovascular coiling is associated with bet-ter 1-yr outcomes, with trends towardsuperior long-term outcomes, whencompared with surgical clipping.

Apart from the recently published in-formation stemming from the ISAT trial,randomized trials comparing long-termoutcomes after coiling vs. clipping of rup-tured aneurysms are not available. How-ever, in an analysis of patients who un-derwent coiling of unruptured aneurysmsand were followed for a median of 22.3months, annual re-bleeding rates were0.8% in the first year, 0.6% in the secondyear, and 2.4% in the third year afterembolization, with no re-bleeding in sub-sequent years (16). In a study of 29 pa-tients with giant aneurysms treated withendovascular coiling and followed up fora median of 50 months, long-term clini-cal outcomes were good in 79% of pa-tients; however, the stability of the coilover time was poor, requiring repeat coil-ing, surgery, or parent-vessel occlusionin more than half of the aneurysms ini-tially treated with coils (17). Finally,Friedman et al. (18) reported clinical(mean, 19.1 months) and angiographic(mean, 11.6 months) data in 83 patientswith aSAHs treated with endovascularcoils. Neurologic outcome was good in77% of patients; however, 26% had a“dog-ear” remnant, 35% had a residualneck, and 3% had residual aneurysm fill-ing. Two or more coiling procedures wererequired in 34% of patients.

An important question concerns theinfluence of surgical or endovasculartreatment on the prevalence of cerebralischemic complications. In several non-randomized comparisons of surgery andendovascular therapy of ruptured aneu-rysms, the rate of symptomatic vaso-

spasm was either not significantly differ-ent (19–21) or slightly higher (22, 23)among surgically treated patients. Anearly nonrandomized study of 156 pa-tients had suggested a higher rate of ce-rebral infarction in patients receiving en-dovascular vs. surgical therapy; however,the proportion of patients with poor ini-tial neurologic presentation was higherin the endovascular group (24).

Comment. The available data indicatethat in patients with good neurologicgrade aSAH who undergo treatment foraneurysms in the anterior circulation,1-yr outcomes are clearly superior afterendovascular coiling when comparedwith surgical clipping. Follow-up of pa-tients receiving endovascular treatmentin some studies suggests that despitegood clinical results, a significant propor-tion of patients may require repeat endo-vascular or surgical therapy for residualor recurrent aneurysmal lesions. How-ever, long-term (�1 yr) clinical trends inpatients enrolled in ISAT do seem to sug-gest that endovascular coiling is likely toretain its advantage over clipping as asuperior procedure, and further fol-low-up of these patients is likely to addinsight to this debate. Preliminary resultsfrom various studies have failed to con-sistently show an association betweentreatment modality and the rate of de-layed cerebral ischemia. For posteriorcirculation aneurysms and for large, an-atomically complex or wide-necked aneu-rysms, further studies are needed to de-fine the best therapeutic approach.

Controversy 2: Diagnosis ofDelayed Cerebral Ischemia

A critical concern in the managementof patients with aSAH is the predictionand accurate diagnosis of delayed cere-bral ischemia because timely institutionof therapeutic interventions may preventthe occurrence of tissue infarction.Spasm of large arteries in the circle ofWillis is a significant determinant of ce-rebral ischemia after aSAH and carries a15–20% risk of stroke or death (25).Four-vessel cerebral digital subtractionangiography is the gold standard for di-agnosing vasospasm, but given the inher-ent risks and allocation of time and re-sources required for this procedure,alternative and complementary diagnos-tic tools have been proposed (26). Theseinclude transcranial Doppler (TCD), com-puted tomographic angiography (CTA),magnetic resonance imaging, radionu-

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clide imaging, cerebral microdialysis, andelectroencephalography.

TCD is an ultrasound-based monitorthat uses the principle that the velocity ofblood flow in an artery is proportional tothe ratio of flow to the luminal surfacearea of that vessel (27). TCD is a nonin-vasive, low-risk procedure that can bereadily performed at the bedside andlends itself to repeated (e.g., daily) obser-vations, enabling trend analysis. How-ever, there is debate about the correlationbetween increased TCD flow velocitiesand a) angiographic vasospasm and b)clinically significant or “symptomatic”vasospasm. Although mean middle cere-bral artery (MCA) cerebral blood flow(CBF) velocities of �200 cm/sec accu-rately predict angiographic vasospasm,velocities in the 120–200 cm/sec rangehave a far lower predictive value (28).Moreover, it has been observed that TCDis not as reliable in estimating distal MCAvasospasm compared with the more prox-imal portions of the MCA (29). Studiesshowing a significant moment-to-mo-ment variability during continuous mea-surement of CBF velocities have height-ened concern about the accuracy of thistechnique (30).

To address these limitations, severalrefinements have been proposed. Investi-gators have suggested that incrementalincreases in CBF velocities over time aremore helpful than velocities taken in iso-lation. One study indicated that an in-crease of �50 cm/sec in 24 hrs wasclosely associated with angiographic andclinical vasospasm (31). To overcome thenumerical dependence of flow velocitiesin the measurement of CBF, Lindegaardet al. (32) developed a “hemispheric in-dex” that normalizes flow velocity in theMCA to that in the ipsilateral extracranialinternal carotid artery (an index of �3 isstrongly predictive of angiographic vaso-spasm). Torbey et al. (33), observing thatangiographic vasospasm occurs at lowerTCD velocities in older patients, sug-gested that the accuracy of TCD can beenhanced by using an age-adjusted no-mogram based on a quadratic relation-ship between age and CBF velocities.Some investigators have proposed thatthe diagnostic capability of TCD may beenhanced by transcranial color-codedsonography. Transcranial color-codedsonography is an ultrasound-based neu-roimaging technique that allows real-time visualization of intracranial vascularstructures in addition to measurement ofCBF velocities. In a prospective study

comparing transcranial color-codedsonography and conventional TCD in theprediction of angiographic spasm, sensi-tivity and specificity of transcranial color-coded sonography for MCA and internalcarotid artery vasospasm were higherthan those for TCD (34). The validity ofTCD in diagnosing angiographic vaso-spasm was summarized in a recent sys-tematic review (35). For the MCA, sensi-tivity of TCD was 67% and specificity was99%, with a positive predictive value of97% and negative predictive value of78%. The accuracy of TCD was consider-ably less for detecting spasm in vesselsother than the MCA.

Interest has developed in CTA as adiagnostic modality for detecting cerebralvasospasm. CTA may be combined withperfusion computed tomography (CT), al-lowing characterization of both vascularanatomy and associated cerebral perfu-sion abnormalities. Using CTA, a positivepredictive value of 100% for angiographicvasospasm was reported in a recent smallseries (36). Another group reported thatCTA was highly accurate in detecting se-vere cerebral vasospasm in proximal ar-terial locations but was less accurate fordetecting mild and moderate spasm indistal locations (37). A third group notedan excellent concordance between the se-verity of vasospasm as determined by CTAand conventional angiography in bothproximal and distal arterial segments(38). Of note, none of these studies in-cluded �20 patients.

Although the phenomenon of cerebralvasospasm has historically elicited muchscientific interest, recent investigationshave turned to the related question ofbrain ischemia and infarction in patientswith aSAH. The predictors of CT-definedcerebral infarction after aSAH were ana-lyzed in a recent study. Multivariate anal-ysis revealed that both TCD and angio-graphic vasospasm were independentlyassociated with cerebral infarction, how-ever there was agreement between thetwo tests only in 73% of cases, and thevalidity of the two tests alone or in com-bination was disappointing (combinedsensitivity, 0.72; specificity, 0.68; positivepredictive value, 0.67; negative predictivevalue, 0.72) (39). These results are con-sistent with data suggesting that thepathophysiologic model of cerebral isch-emia after aSAH may need to considerfactors other than large artery spasm.

Magnetic resonance diffusion-weighted imaging accurately identifiesbrain tissue that is at high risk of infarc-

tion, whereas perfusion-weighted imag-ing reveals asymmetries in regional per-fusion. In a study of 14 patients withaSAH, diffusion-weighted imaging abnor-malities were noted in all patients withvasospasm suggested by TCD, whereas nosuch abnormalities were observed in pa-tients without abnormal TCD findings(40). A study of aSAH patients using per-fusion-weighted imaging revealed areasof hypoperfusion that correlated wellwith delayed ischemic neurologic deficits(DIND) and were larger than the areas ofdiffusion-weighted imaging abnormalityperformed at the same time. Of note,whereas all 15 patients with DINDshowed alterations in perfusion-weightedimaging, TCD evidence of vasospasm wasnoted in only seven of these patients (41).

Radionuclide-based studies of CBFand metabolism include single-photonemission computed tomography (SPECT)and positron emission tomography. In aseries of 129 patients with aSAH, Rajen-dran et al. (42) found that 89 had SPECTevidence of hypoperfusion, and this cor-related with TCD evidence of vasospasmin only 64% of cases. In another study,Jabre et al. (43) observed that the sensi-tivity of SPECT for symptomatic vaso-spasm was inferior to TCD; however,SPECT was more specific. Studies usingpositron emission tomography in pa-tients with aSAH suggest this techniquecan help differentiate neurologic deficitsdue to reversible ischemia or to irrevers-ible infarction (44); however, the accu-racy of positron emission tomography(45) in the diagnosis of vasospasm is un-known.

Monitoring of neurochemical markersof ischemia with cerebral microdialysishas been proposed as a technique for de-tecting vasospasm and delayed cerebralischemia. In a study of 97 patients withaSAH, neurochemical changes indicativeof ischemia were observed before the on-set of symptoms in 83% of patients withDIND (46). In another report, an isch-emic pattern of cerebral metabolites pre-ceded the occurrence of DIND by a meaninterval of 11 hrs (47). In a comparisonwith TCD and angiography, microdialysiswas found to have the highest specificityand likelihood ratio, but lower sensitivity,as a diagnostic tool for DIND (48). In astudy of 13 patients combining cerebralmicrodialysis and positron emission to-mography, it was noted that transientreductions in regional CBF correlatedwith elevations in extracellular glutamateand glycerol, whereas the lactate/pyru-

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vate ratio was sensitive only after longerperiods of hypoperfusion (49). Althoughthese results are encouraging, several in-herent limitations of cerebral microdialy-sis have been recognized, including thedifficulty of extrapolating from measure-ments made in a very restricted volumeof tissue, the development of reactive gli-osis around the catheter tip decreasingthe accuracy of measurements, the inter-subject variability in basal neurochemicalvalues, and the tissue trauma after probeimplantation (50). The use of this tech-nique as a routine diagnostic method inpatients with aSAH was not supported ina recent systematic review (51).

Several groups have assessed the roleof electroencephalography in the diagno-sis of cerebral ischemia after aSAH. In astudy of 151 patients, Rivierez et al. (52)noted that that focal areas of slowingcorrelated with angiographic vasospasmin 96% of cases. Vespa et al. (53), usingcontinuous electroencephalography,found that relative alpha variability wasdecreased in 19 patients with angio-graphically proven vasospasm; in ten ofthese patients, the relative alpha variabil-ity change preceded clinical symptoms bynearly 3 days. Finally, Claassen et al. (54),in comparative-analysis quantitative elec-troencephalographic variables in 34 pa-tients with Hunt and Hess grade IV or VaSAH, determined that a decrease in al-pha to delta ratio (ADR) was stronglyassociated with delayed cerebral ischemiadefined by clinical or CT criteria. In thisreport, a 50% decrement in alpha to deltaratio has a sensitivity of 89% and a spec-ificity of 84% for delayed cerebral isch-emia.

Comment. The prediction and accu-rate diagnosis of cerebral ischemia is acardinal goal in the critical care of pa-tients with aSAH. Using serial TCD andtranscranial color-coded sonography, in-cremental changes in flow velocities andcalculation of the hemispheric index mayprovide valuable information with regardto underlying angiographic vasospasm, inparticular, vasospasm involving the MCA.The diagnostic capability of CTA is un-clear and needs investigation in a pro-spective study. Recent studies haveshifted away from the characterization ofvessel lumen diameter to the detection ofchanges in CBF and of cerebral ischemia.Perfusion CT, diffusion- and perfusion-weighted magnetic resonance imaging,radionuclide-based perfusion studies, ce-rebral microdialysis, and electroencepha-lography hold promise as techniques that

might expand the therapeutic window fortreating ischemia in patients with aSAH;however, their introduction into clinicalpractice needs further confirmation inclinical trials.

Controversy 3: Management ofDelayed Cerebral Ischemia

The principal options for treating de-layed cerebral ischemia are hemody-namic augmentation and endovasculartherapy. Alternative therapies include in-traaortic balloon counterpulsation(IABC), therapeutic hypothermia, andbarbiturate coma.

The concept of hemodynamic aug-mentation—also referred to as hyperten-sion, hypervolemia, hemodilution or tri-ple-H therapy—in patients with aSAHevolved out of two important and (andrelated) observations. The first, suggestedin studies from the 1950s and 1960s, wasthe strong association between cardiovas-cular variables, such as intravascular vol-ume status, cardiac output, and bloodpressure in the days and weeks ensuingaSAH, and clinical outcomes, such assymptomatic vasospasm and long-termneurologic function. The second observa-tion was that cerebral vasospasm is char-acterized by a shift in cerebrovascularresistance away from the penetrating ar-terioles to the major branches of the cir-cle of Willis and their proximal branches,vessels that are incapable of effective au-toregulation. As a result, CBF becomespassively dependent on systemic bloodpressure, greatly increasing the risk ofcerebral ischemia. Using the Poiseuillerelationship, it can be predicted that ef-forts to increase systemic blood pressureor to decrease blood viscosity will ame-liorate cerebral perfusion and reverseischemia (55).

In an early case series of patients withDIND, Kosnik and Hunt noted significantimprovements in neurologic function af-ter initiating therapy with phenylephrineand colloid fluid expansion (56). This wasfollowed by several other uncontrolledstudies further substantiating the clinicalefficacy of hemodynamic augmentation(57–60). Randomized studies evaluatingthe efficacy of hemodynamic augmenta-tion therapy in aSAH are limited in num-ber. In 30 aSAH patients who were beingstudied before they underwent aneurysmclipping, Rosenwasser et al. (61) notedthat a strategy of blood pressure controlwith vasodilators in addition to volumeexpansion with packed red blood cell

transfusion and albumin was associatedwith a significantly lower rate of symp-tomatic vasospasm and death when com-pared with a strategy of blood pressurecontrol with diuretics. Lennihan et al.(62) randomly assigned 82 aSAH patientson the day after aneurysm clipping toreceive albumin fluid boluses titrated tonormal or high cardiac filling pressures(central venous and pulmonary artery di-astolic pressures). They discovered thathigher filling pressures were not associ-ated with any significant change in CBF(as measured by xenon CT) or blood vol-ume, nor were there any differences inthe rate of symptomatic vasospasm, cere-bral infarction, or 3-month Glasgow Out-come Scale. Finally, in a study of 32 aSAHpatients randomized to hypertensive/hypervolemic vs. normotensive/normo-volemic management protocols, Egge etal. (63) reported no difference in vaso-spasm rates, CBF as measured by SPECT,or 1-yr Glasgow Outcome Scale, whereasa higher rate of complications (hemor-rhage, coagulopathy, congestive heartfailure) was noted in the hypertensive/hypervolemic group. When the results ofthese three trials were pooled in a sys-tematic review, no significant effect ofprophylactic triple-H therapy on the rateof symptomatic vasospasm, DIND, ordeath was noted (64). A Cochrane meta-analysis reached a similar conclusion (9).

Triple-H therapy has many inherentlimitations, notably a) the association ofhemodynamic augmentation with severecomplications such as congestive heartfailure, noncardiogenic pulmonaryedema, myocardial ischemia, intracranialhemorrhage, global cerebral edema, anddeath; b) failure to reverse neurologicdeterioration in certain patients; and c)contraindications to its use such as thepresence of significant preexisting or ac-quired cardiopulmonary dysfunction. Al-ternative approaches to treating vaso-spasm have emerged, including a) astrategy targeting cardiac output ratherthan mean arterial pressure as a physio-logic end point, b) the endovascular ther-apies, including balloon angioplasty andintraarterial vasodilator administration,and c) the use of IABC.

To augment cardiac output, the ino-tropic agent dobutamine was adminis-tered in combination with hypervolemicpreload enhancement to 23 patients withvasospasm whose neurologic examina-tion failed to improve after preload en-hancement alone. The authors noted a52% increase in cardiac index, and clini-

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cal reversal of ischemic symptoms wasevident in 18 of the 23 patients (65). In amore recent study, xenon CT was used toevaluate CBF in 16 patients with symp-tomatic vasospasm who underwent vol-ume expansion combined with eithermean arterial pressure augmentationwith phenylephrine or cardiac outputaugmentation with dobutamine. The in-crease in mean CBF was similar in bothgroups (66). The mechanism whereby in-creases in cardiac output withoutchanges in mean arterial pressure affectCBF is unclear, and this phenomenonmay be unique to the setting of vaso-spasm, as a relationship between cardiacoutput and CBF was not observed in pa-tients with traumatic brain injury (67). Ithas been postulated that the wider pulsepressure and enhanced pulsatile flow as-sociated with the administration of ino-tropic agents may ameliorate flowthrough collateral vessels and throughthe microvasculature (68).

Recent years have seen a significantdevelopment in the use of endovasculartherapies for patients with, or at risk of,cerebral vasospasm (69). Endovasculartreatments include transluminal balloonangioplasty (TBA) and the intraarterialdelivery of vasodilating compounds.These techniques are most commonlyused in patients with symptomatic vaso-spasm that has been resistant to triple-Htherapy. TBA is highly effective in reliev-ing focal spasm involving proximal seg-ments of the circle of Willis; however,when vasospasm is diffuse or more distal,the selective intraarterial infusion of va-sodilators may be helpful. Clinical im-provement after angioplasty is well doc-umented and is generally durable,whereas the response to intraarterial va-sodilators is transitory. Complications ofTBA include trauma to the arterial wallleading to dissection, rupture, andthrombosis, with consequent cerebral in-farction or hemorrhage; in addition,reperfusion of cerebral tissue in whichinfarction has already occurred may in-duce edema and hemorrhage. The mostcommonly administered cerebral intraar-terial vasodilator is papaverine. However,papaverine is neurotoxic and has beenlinked to seizures, coma, blindness, andirreversible cortical injury (70). Vera-pamil (71), nimodipine (72), and nicardi-pine (73) have been used as alternativeintraarterial cerebral vasodilators; how-ever, data on their efficacy and safety islargely anecdotal.

Although the efficacy of TBA in treat-ing vasospasm is well documented, inter-est has developed on the preventive use ofthis technique in high-risk patients.Based on results from an animal modelshowing that TBA performed on the dayof the hemorrhage prevented the devel-opment of angiographic spasm on day 7after aSAH, Muizelaar et al. (74) evalu-ated prophylactic TBA in 13 patients withFisher grade III aSAH who had a highprobability of developing vasospasm. Ofthese patients, none developed DIND ormore than mild TCD-defined vasospasm.At 3 months posttreatment, eight pa-tients had a good recovery, two weremoderately disabled, and three had died(one because of a vessel rupture duringTBA). These authors are conducting arandomized trial (Balloon Prophylaxis ofAneurysmal Vasospasm trial; see http://www.strokecenter.org/trials for details)to determine whether the efficacy of pro-phylactic TBA is sufficient to justify therisks and to clarify which vessels need tobe dilated prophylactically

In recent years, several groups havereported on the use of IABC in patientswith delayed cerebral ischemia (75–79).IABC has been associated with reversal ofneurologic deficits and significant in-creases in CBF in patients who did notrespond to conventional triple-H therapy(79) or who had cardiopulmonary dys-function contraindicating it (75, 76). Ofnote, despite the invasive nature of thistechnique, the prevalence of severe ad-verse effects was remarkably low, and arecent series evaluated the prophylacticplacement use of IABC in six patients whowere considered at high risk for cerebralvasospasm (77). As with pharmacologiccardiac output augmentation, the benefi-cial effects of IABC are not well under-stood and might reflect augmentation ofdiastolic perfusion through the carotidand vertebral arteries and heightenedpulsatility, which has been associatedwith improved microvascular blood flow(78).

Comment. Hypovolemia and hypoten-sion after aSAH are strongly linked toadverse outcome and should be avoidedin all patients. The existing data do notsupport the prophylactic use of triple-Htherapy in patients with aSAH who do nothave clinical evidence of vasospasm. Inpatients with symptomatic vasospasm,hemodynamic augmentation may reverseneurologic deterioration; however, an ad-equately powered randomized trial isneeded to test the hypothesis that tri-

ple-H therapy has a favorable effect onneurologic outcomes or survival and issafe when compared with a strategy ofnormovolemia and normotension. Fur-ther study is needed to better understandthe effects of increased cardiac output, asopposed to hypertensive therapy, on CBFand on the reversal of symptomatic vaso-spasm. At this time, TBA and intraarterialvasodilators administration are reason-able options in treating vasospasm refrac-tory to medical management. However,the relative efficacy and harm of TBA vs.medical management needs further sub-stantiation. This might take the form of arandomized trial comparing immediateangioplasty vs. triple-H therapy in pa-tients who have developed symptomaticvasospasm. In patients with symptomaticvasospasm in whom triple-H therapy andendovascular options have either failed orare contraindicated, consideration shouldbe given to IABC or to neuroprotectiveinterventions such therapeutic hypother-mia and pentobarbital coma (see below).

Controversy 4: CerebralProtection

The development of cerebral ischemiccomplications in a significant proportionof patients after aSAH has prompted greatinterest in the possibility of preventing orlimiting irreversible brain injury. Therisk of a cerebral ischemic event is par-ticularly high during specific events as-sociated with aSAH, namely a) the initialaneurysmal rupture (risk of global cere-bral ischemia secondary to increased in-tracranial pressure, hypotension, and hy-poxemia), b) the procedure undertakenfor securing the aneurysm (risk of strokein relation to surgical clipping or endo-vascular coiling), and c) delayed cerebralischemia and vasospasm. Cerebral pro-tective strategies that have been studiedin these settings include a) pharmaco-logic agents with cytoprotective or vaso-dilatory properties, b) therapeutic hypo-thermia, and c) hemodynamicaugmentation or endovascular therapies,which are discussed above. Pharmaco-logic cerebral protectants that have beentested in clinical studies of aSAH includecalcium channel antagonists, tirilazadmesylate, glucocorticoids, magnesium,endothelin receptor antagonists, and hy-droxymethylglutaryl coenzyme A reduc-tase inhibitors.

A meta-analysis of trials using calciumchannel antagonists after aSAH was re-ported by the Cochrane group (8). Of 11

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studies (2,804 patients), eight involvednimodipine (1,574 patients), two involvednicardipine (954 patients), and one in-volved AT877 (276 patients). When com-pared with placebo, calcium channel an-tagonists were associated with asignificantly reduced risk of poor out-come, with a relative risk (RR) of 0.82(95% confidence interval [CI], 0.72–0.93), an absolute risk reduction of 5.1%,and numbers needed to treat of 20. Theresults were most robust for oral nimo-dipine (RR of poor outcome, 0.70; 95%CI, 0.58–0.84). The RR of death in pa-tients treated with calcium antagonistswas 0.94 (95% CI, 0.80–1.10), that ofischemic neurologic deficits was 0.67(95% CI, 0.59–0.76), and that of CT orMR documented cerebral infarction was0.80 (95% CI, 0.71–0.89). Of note, theprevalence of angiographic vasospasmwas not influenced by treatment alloca-tion, suggesting that the benefit of nimo-dipine was linked to its cytoprotectiverather than its cerebral vasodilatory prop-erties. The effects of nimodipine on aSAHoutcome are fairly consistent across pub-lished trials. However, it is plausible thatthe results were confounded because ni-modipine-treated patients may have re-ceived greater amounts of intravenousfluids to counteract the effect of the drugon systemic blood pressure, surrepti-tiously exposing them to a more aggres-sive regimen of triple-H therapy.

Tirilazad mesylate, a non–glucocorti-coid 21-aminosteroid that inhibits lipidperoxidation, has been evaluated in fourrandomized, placebo-controlled trials ofpatients with aSAH. The first trial, con-ducted in Europe and Australasia, dem-onstrated an improvement in symptom-atic (but not angiographic) vasospasm,3-month survival, and Glasgow OutcomeScale in patients receiving 6 mg/kg tiril-azad for 10 days (80). These results werenot reproduced in a second study under-taken in North America in which tirilazadadministration had no significant effecton symptomatic vasospasm, 3-monthmortality, or Glasgow Outcome Scale(13). The divergence in these results wasbelieved to reflect differences in manage-ment protocols, including the widespreaduse of anticonvulsants (e.g., phenytoin)in the American trial, which may havediminished the bioavailability of tirilazad.Further analysis of these two studies in-dicated that any detected improvement inoutcome seemed limited to men. This ledto two other studies conducted in womenonly. The first of these demonstrated a

rate of symptomatic vasospasm that wassignificantly lower in women who re-ceived tirilazad, 15 mg/kg, without anyeffect on mortality (81). In the other trial,the rate of symptomatic vasospasm wasnot affected by tirilazad therapy; however,mortality was significantly lower intreated patients with Hunt and Hessgrades IV and V (82). When results of thefour trials were combined in a meta-analysis, it was concluded that overallmortality was decreased in patients whoreceived tirilazad, with an effect thatseemed most pronounced in patientswith poor neurologic grade (83).

Animal studies have shown that glu-cocorticoids may effectively prevent de-layed cerebral ischemia after aSAH (84–86). The potential benefit ofglucocorticoids in humans was suggestedin a nonrandomized comparative study of21 patients by Chyatte et al. in whichpatients receiving high-dose methylpred-nisolone had a significantly lower rate ofDIND (87). However, these results havenot been reproduced in any other clinicaltrial.

The neuroprotective effects of magne-sium have been reported in experimentalmodels of traumatic brain injury, cere-bral ischemia, and aSAH. Magnesium sul-fate therapy is both safe and effective inpreventing neurologic complications inobstetric patients with preeclampsia. Arandomized trial of 40 patients demon-strated that high-dose intravenous mag-nesium sulfate is safe in patients withaSAH (88). In a more recent randomized,placebo-controlled trial of 283 patients,an infusion of magnesium started within4 days of aSAH and continued up to 14days postaneurysm occlusion was associ-ated with a 34% RR reduction for theprimary outcome of delayed cerebralischemia, however, this result did notachieve statistical significance (89). Ofnote, significantly more patients treatedwith magnesium had excellent outcome(defined as a Rankin score of 0) at 3months (RR, 0.91; 95% CI, 0.84–0.98).

Following experimental evidence im-plicating the vasoconstrictor endothelinpeptides and their receptors in the patho-physiology of cerebral vasospasm, a ran-domized, placebo-controlled trial of anendothelin receptor antagonist, TAK-044,was conducted in 412 patients with aSAH(90). A nonsignificant decrease in the rateof delayed cerebral ischemia was noted inthe treated group. A more recent obser-vational study suggested that increasedCSF levels of endothelin did not correlate

with vasospasm but were a more generalmarker of neuronal damage (91).

Initially developed as cholesterol-lowering agents, the hydroxymethylglu-taryl coenzyme A reductase inhibitors orstatins are capable of modulating endo-thelial function by reducing vascular in-flammation, inhibiting vascular smoothmuscle cell proliferation, decreasingplatelet aggregation, and promoting NO-mediated cerebral vasodilation (92). In amurine model of aSAH, pretreatmentwith simvastatin was associated with areduction in vasospasm and with in-creased expression of NO synthetase (93).A retrospective review of 60 aSAH pa-tients suggested that patients who weretaking statins, when compared with acontrol group who were not, had a sig-nificantly lower rate of DIND and cerebralinfarctions of any type, but no impact onmortality or global outcome (modifiedRankin scale) was detected (94). Anotherretrospective study showed an increasedrisk of vasospasm associated with use ofstatins (95). The effects of statins havebeen further explored in two recent ran-domized, placebo-controlled trials. In thefirst, therapy with simvastatin (19 pa-tients) initiated within 48 hrs of aSAHwas linked to reduced serum levels ofbrain injury biomarkers and a decrease inthe prevalence of DIND confirmed byTCD or angiography when compared withplacebo (20 patients) (96). In the second,treatment with pravastatin started within72 hrs of aSAH ameliorated cerebral va-sospasm, improved cerebral autoregula-tion, and reduced vasospasm-relatedDIND by 83% and mortality by 75% (97).Additional agents that have generated in-terest as cerebral protectants after aSAHinclude erythropoietin (98), nitric oxidedonors (99), and potassium channel acti-vators (100); to our knowledge, there areno published clinical trials of these com-pounds in patients with aSAH.

The neuroprotective effect of hypo-thermia is supported by a large body ofexperimental and clinical evidence. Thiseffect may result from decreased excita-tory amino acid release and free-radicalproduction, reduced intracellular cal-cium accumulation, stabilization of theblood–brain barrier, and decreased cere-bral edema (101). Hypothermia also hasserious deleterious consequences, includ-ing cardiovascular depression, immunesuppression, coagulopathy, and electro-lyte abnormality. The use of moderatehypothermia (28–32°C) to protect thebrain during cerebral aneurysm surgery

516 Crit Care Med 2006 Vol. 34, No. 2

was first described in the 1950s; however,interest in this technique declined inlight of very poor clinical outcomes. Morerecently, several studies have evaluatedmild hypothermia (38–35°C) as a protec-tive strategy during aneurysm surgery. Inan early randomized trial, 114 patientswith ruptured and unruptured intracra-nial aneurysms who received mild intra-operative hypothermia had a lower rate ofneurologic deterioration at 24 and 72 hrsafter surgery, a greater frequency of dis-charge to home, and a greater rate ofgood long-term outcomes (102). How-ever, a subsequent multiple-center studyof 1,001 patients with aSAH who hadWorld Federation of Neurologic Surgeonsscores of I, II, or III failed to detect anybeneficial effect of intraoperative coolingon 3-month neurologic outcomes or onany perioperative outcomes (103). Mov-ing beyond the perioperative setting,small-scale investigations indicate thatmild hypothermia may be helpful in casesin which vasospasm is refractory to con-ventional treatment (104, 105). The ef-fects of hypothermia on the relationshipbetween CBF and cerebral metabolic ox-ygen demand in patients with aSAH arepoorly understood. Hypothermia was as-sociated with evidence of brain ischemiain one study (106), but another study didnot confirm this finding (107).

Comment. Although considerable re-search has focused on the possibility ofneuroprotection in patients with aSAH,only oral nimodipine has been clearly as-sociated with improved outcome. Meta-analysis suggests a survival benefit withhigh-dose tirilazad mesylate in patientswith poor neurologic grade. Preliminaryresults with magnesium and statins needsubstantiation in larger randomized pla-cebo-controlled trials. Finally, no benefitwas seen for intraoperative mild hypo-thermia in aSAH patients with good neu-rologic grade; however, further studiesare needed to explore other methodolo-gies and applications of therapeutic hypo-thermia, for example, more prolongedcooling protocols and its effects on pa-tients with poor neurologic grade or re-fractory vasospasm.

Controversy 5: AntithromboticAgents

Although the conventional view of an-eurysmal rupture emphasizes the patho-physiologic role of hemorrhage and theneed to prevent recurrent intracranialbleeding, data have accrued to suggest

that clot formation, both in the intravas-cular and extravascular compartments, isa key determinant of cerebral injury afteraSAH. The presence of a thick clot in thesubarachnoid space is consistently re-ported as one of the strongest predictorsof vasospasm after aSAH (108). The poorneuroanatomic correlation between ra-diologically defined vasospasm and cere-bral infarction suggests alternate or com-plementary hypotheses of DIND, amongwhich intravascular thrombosis is a pos-tulated mechanism.

Thorombolytics. Experimental andclinical evidence indicate that a sub-arachnoid clot may be removed with thehelp of thrombolytic agents. Cisternal ir-rigation with recombinant tissue plas-minogen activator was found to be safe(109), and intrathecal urokinase infusionhas been associated with a decreased rateof vasospasm and permanent neurologicdeficits (110). A systematic review of ninestudies (only one of which was random-ized) noted that cisternal thrombolysiswas associated with an absolute risk re-duction of 14.4% for DIND (p � .001),9.5% for poor Glasgow Outcome Scalescores (p � .01), and 4.5% for death (p �.05) (111). Treatment effects did not sig-nificantly differ among the studies on thebasis of the type of thrombolytic agentused (recombinant tissue plasminogenactivator vs. urokinase) or the method ofadministration (intraoperative vs. postop-erative). Studies that enrolled only pa-tients at high risk for vasospasm seemedto demonstrate greater treatment effects(109). In an intriguing recent trial,Hamada et al. (110) randomized 110 pa-tients to endovascular coiling with orwithout infusion of urokinase into thesubarachnoid space via a microcatheterinserted in the lumbar space. The rate ofsymptomatic vasospasm was 8.8% in theurokinase-treated group vs. 30.2% in theuntreated group (p � .012).

Anticoagulants. Heparin, an anti-thrombin III agonist, has biological prop-erties that include anticoagulation, modu-lation of inflammation, neuroprotection,and antiproliferative effects. In an animalmodel of aSAH, administration of heparinhas been associated with smooth musclerelaxation, increased CBF, and a reductionin proliferative angiopathy (112). A recentrandomized, placebo-controlled trial thatenrolled 120 patients indicated that low-molecular-weight heparin significantly re-duced the rate of vasospasm-related cere-bral infarction (3.5% of enoxaparin-treatedpatients and 28.3% of placebo-treated pa-

tients, p � .001), without any increase inthe rate of intracranial bleeding (113).There was a potential bias because patientsin the placebo group were more severelyaffected (worse Hunt and Hess grade). Ofnote, another larger randomized trial of170 patients suggested that enoxaparin hadno effect on the outcome of aSAH andseemed to increase the risk of intracranialhemorrhage (114).

Antiplatelet Agents. Platelet aggrega-tion and release of thromboxanes havebeen demonstrated after aSAH, and thesechanges are more pronounced in patientswho develop DIND (115). These data, incombination with the identification ofmicroembolic signals by TCD in patientswith aSAH (116), have prompted severalsmall clinical trials examining the thera-peutic potential of antiplatelet agents.Meta-analysis of these results indicatedthat in patients treated with aspirin orantiplatelet agents, the RR of DIND wassignificantly reduced (RR, 0.65; 95% CI,0.47–0.89), without a concomitant in-crease in the risk of intracranial hemor-rhage. There was also a trend toward areduced risk of poor outcome in patientsreceiving antiplatelet agents (RR, 0.87;95% CI, 0.65–1.17) (117).

Comment. Preliminary data indicatethat placement of thrombolytic agents inthe subarachnoid space may improve out-come after aSAH, but adequately pow-ered, randomized, controlled studies areneeded to substantiate these findings.The two randomized trials assessing theassociation between low-molecular-weight heparin and aSAH outcome arecontradictory. Regarding antiplatelettherapy, although a beneficial effect issuggested, the evidence does not supportthe routine use of these agents in aSAH atthe present time. Randomized trials withgreater power would be needed to clarifythe role of these therapies.

Controversy 6: SeizureProphylaxis

Aneurysmal SAH has been linked to anincreased risk of seizures, yet the role ofseizure prophylaxis is controversial. In aretrospective analysis of 217 surgicallytreated patients with aSAH over a 2-yrperiod, 20% experienced one or more sei-zures, with more than half of these oc-curring in the perioperative period; ofnote, the occurrence of perioperative sei-zures did not predict epilepsy in thisstudy (118). Another investigation re-vealed that 24 of 121 aSAH patients with

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Table 1. Summary of controversies in the management of aneurysmal subarachnoid hemorrhage (SAH)

Controversy Best Available Evidence and Recommendations Future Studies

Surgical vs. endovascular aneurysmexclusion

Level I evidence in favor of endovascularmanagement (grade A)

Comparative long-term follow-up of endovascular vs.surgical patients. New randomized trials to testendovascular vs. surgical therapy in patient subsetsthat were not represented in the ISAT trial.

Diagnosis of vasospasmTranscranial Doppler (TCD) Level III evidence for high PPV and specificity of

TCD for MCA (grade C)Prospective study comparing predictive value of CTA

and TCD with angiography in detecting vasospasm.Computerized tomography angiography

(CTA)Level III comparing CTA to angiography and TCD

(grade C)Observational study to compare CTA/CT perfusion,

perfusion/diffusion weighted MRI, and conventionalangiography in detecting clinically significant vasospasm.

MRI, PET, SPECT Level V evidence (grade C)Cerebral microdialysis Level V evidence Prospective clinical studies to understand the

correlation between neurochemical abnormalities andclinical events in SAH. Outcome-based trials to assessthe effect of microdialysis-guided management.

Treatment of vasospasmVasospasm prophylaxis Level II evidence showing no effect of triple-H

prophylaxis on DIND (grade B)Prospective randomized study comparing outcomes in

patients in vasospasm receiving either triple-Htherapy or undergoing immediate endovascularintervention. Prospective studies to identify high-risk patients who may be candidates forprophylactic management of vasospasm.

Vasospasm treatment Level III evidence supporting use of hemodynamicaugmentation as treatment of vasospasm (gradeC)

Adequately powered prospective, randomized trialevaluating hemodynamic augmentation vs.conventional hemodynamic goals in symptomaticvasospasm. Prospective, randomized trials tocompare a strategy of cardiac output augmentationvs. arterial pressure augmentation.

Hemodynamic end points Level IV evidence for use of cardiac output goalsover arterial pressure goals for hemodynamicaugmentation (grade C)

Intraaortic balloon counterpulsation (IABC) Level IV evidence for use of IABCNeuroprotection

Ca� channel blockers Level I evidence favoring use of nimodipine andagainst use of nicardipine and AT877 (grade A)

Search for alternative neuroprotectants based onanimal studies for possible synergy with orsuperiority to nimodipine.

Tirilazad mesylate Level II evidence in favor of tirilazad for highgrade SAH (grade A)

Glucocorticoids, magnesium,endothelin receptor antagonists, andhydroxymethylglutaryl coenzyme Areductase inhibitors

Level II evidence for statins, magnesium (grade B) Randomized, placebo-controlled study of these agentsin patients with aneurysmal SAH; largerrandomized trials evaluating statins and magnesiumin SAH.

Level V evidence favoring use of other agents(grade C)

Hypothermia Level I evidence showing no benefit ofintraoperative hypothermia (grade A); use inother settings unclear

Prospective, randomized studies to define the role ofhypothermia in patients at high risk to developvasospasm (prophylaxis) or in patients with clinicalvasospasm.

Thrombolytics Level IIa evidence for use of thrombolytics (gradeB)

Prospective, randomized trials with sufficientstatistical power to detect the efficacy of antiplateletagents, anticoagulants, and intraoperativethrombolytics with appropriate end points(recurrent hemorrhage, DIND, mortality, andmorbidity/functional outcome).

AnticoagulationAntiplatelet agents Level IIb evidence in favor of use of antiplatelet

agents (grade B)Seizure prophylaxis Level V evidence in favor of prophylaxis Randomized, placebo-controlled studies of

anticonvulsants in aneurysmal SAH with riskstratification based on grade of SAH, location ofaneurysm, and surgical intervention (craniotomy).

Level III evidence against prophylaxis (grade C)Cardiac sequelae of SAH

Myocardial dysfunction Level III evidence in favor of adrenergic receptorblockade

Level IV evidence in favor of inotropic support or IABC

Prospective, observational studies to identifypathophysiology, diagnosis, management, and outcomeof neurocardiogenic injury and to distinguish from otherforms of myocardial dysfunction.

ISAT, International Subarachnoid Aneurysm Trial; MRI, magnetic resonance imaging; PET, positron emission tomography; SPECT, single-photonemission computed tomography; PPV, positive predictive value; MCA, middle cerebral artery; CT, computerized tomography; triple-H, hypertension/hypervolemia/hemodilution therapy; DIND, delayed ischemic neurologic deficits.

aIntervention decreased DIND and improved neurologic outcomes but not mortality rates; bintervention decreased DIND but did not improve neurologicoutcome.

518 Crit Care Med 2006 Vol. 34, No. 2

clipped aneurysms had at least one sei-zure and that ten patients had two ormore seizures after hospital discharge(119). Seizure risk has been linked to thethickness of the aSAH clot (120), to loca-tion of the aneurysm on the MCA (121),to the presence of a subdural hematoma,and to cerebral infarction (122). In onestudy, variables associated with the devel-opment of epilepsy were, in order of im-portance, a history of hypertension, cere-bral infarction, and duration of impairedconsciousness after the seizure (123).

Although empirical prophylaxis of sei-zures after aSAH might seem reasonable,the benefit of preventive anticonvulsantadministration has yet to be demon-strated in a prospective randomized trial.A cohort study of 123 aSAH patients fol-lowed up at 4 to 7 yrs found no evidencefor the effectiveness of prophylactic anti-convulsants (119). A recent retrospectiveevaluation of 527 patients with aSAH in-dicated a strong association between phe-nytoin exposure in the setting and func-tional and cognitive disability (124). In astudy of 101 patients with aSAH who hadunexplained coma or neurologic deterio-ration, eight (all of whom were receivingprophylactic anticonvulsants) were foundto be in nonconvulsive status epilepticus.Despite successful termination of sei-zures in five of eight patients, all eightpatients eventually died after a period ofprolonged coma (125).

Comment. The available evidence sug-gests that prophylaxis of seizures may beuseful in aSAH patients with stroke orother distinct focal pathology. Indiscrim-inate administration of anticonvulsantsto patients with aSAH has been linkedwith unfavorable functional and cognitiveoutcomes. A randomized, placebo-con-trolled trial is warranted to assess theeffect of anticonvulsant prophylaxis onthe prevalence of early and late seizuresin patients with aSAH. Such a trial wouldideally incorporate predefined stratifica-

tion based on focal parenchymal pathol-ogy, aneurysm location, aSAH grade, age,and history of hypertension.

Controversy 7: Cerebral SaltWasting Syndrome

Hyponatremia occurs in up to 30% ofpatients after aSAH and has been associatedwith several disorders, most notably cere-bral salt wasting (CSW) syndrome and thesyndrome of inappropriate antidiuretichormone (SIADH) secretion (126). CSW in-volves renal salt loss leading to a negativesodium balance, hyponatremia, and intra-vascular volume depletion, whereas SIADHis characterized by an inability to appropri-ately excrete free water, resulting in a euv-olemic or hypervolemic state. Becausetherapeutic interventions for CSW and SI-ADH are radically opposed, clinical differ-entiation between the two entities is essen-tial. It has been suggested thathypouricemia and an increased fractionalexcretion of uric acid are more consistentwith a diagnosis of CSW (127). However,physiologic indicators of intravascular vol-ume are generally viewed as the most reli-able way to distinguish between these con-ditions (128).

The pathogenesis of CSW is poorly un-derstood (129). The main pathologic pro-cesses that have been linked with thisderangement are a) decreased sympa-thetic input to the kidney leading to adeficient regulation of proximal tubulesodium resorption and to an inadequaterise in renin and aldosterone in responseto hypovolemia, and b) increased levels ofcirculating natriuretic peptides. The na-triuretic peptides are produced in theheart, brain, and endothelium and pro-mote vasodilation, sodium excretion, anddiuresis. Several groups have demon-strated an association between aSAH, hy-ponatremia, volume depletion, and in-creased blood natriuretic peptide levels,in particular B-type natriuretic peptide

(BNP) (130–133). Others have observed alink between increased levels of BNP andthe development of cerebral vasospasm(134, 135). Recent work suggests thatcardiac dysfunction (136) and triple-Htherapy (137) are factors that might stim-ulate BNP release after aSAH. When theseresults are considered collectively, it re-mains unclear whether the relationshipbetween increased BNP levels and the de-velopment of CSW or vasospasm is caus-ative or merely circumstantial.

Therapeutic options for CSW are lim-ited. It has been argued that increasingsalt intake during CSW only further en-hances sodium excretion. The mineralo-corticoid fludrocortisone, which acts di-rectly on the kidney tubules to enhancesodium resorption, has been shown toprevent intravascular volume depletionin patients with aSAH (138). In a relatedstudy, Hasan et al. (139) found that 0.2mg of fludrocortisone given intrave-nously or orally twice a day in 46 patientswith aSAH significantly reduced the fre-quency of a negative sodium balance andled to smaller decreases in plasma vol-ume and, consequently, less risk of cere-bral ischemia. More recently, Moro et al.(140) demonstrated that hydrocortisoneattenuated excessive natriuresis in thesetting of aSAH with development of hy-ponatremia in 43% of treated patients vs.0% in the untreated group.

Comment. Although the pathogenesisof CSW needs clarification, its conse-quences of hyponatremia and intravascu-lar volume depletion can be deleteriousin the setting of aSAH. Preliminary datasupport the careful use of salt-conservingmedications such as fludrocortisone orhydrocortisone in patients with aSAH.

Controversy 8: Management ofCardiac Dysfunction After aSAH

A spectrum of cardiac sequelae havebeen described in patients after aSAH,

Table 2. Levels of evidence and strength of recommendation

Level of evidenceLevel I Data from randomized trials with low false-positive (�) and low false-negative (�) errorsLevel II Data from randomized trials with high false-positive (�) or high false-negative (�) errorsLevel III Data from nonrandomized concurrent cohort studiesLevel IV Data from nonrandomized cohort studies using historical controlsLevel V Data from anecdotal case series

Strength of recommendationGrade A Supported by level I evidenceGrade B Supported by level II evidenceGrade C Supported by levels III–V evidence

Adapted from Cook et al. (157) and Broderick JP et al (158).

519Crit Care Med 2006 Vol. 34, No. 2

including electrocardiographic changes,reversible cardiomyopathy (stunned myo-cardium), and release of cardiac-specificmarkers (141, 142). Aneurysmal SAH hasalso been linked to hypoxemic respiratoryfailure, which may take the form of con-gestive heart failure, neurogenic pulmo-nary edema, or acute lung injury (143).Extracerebral organ dysfunction in aSAHhas been associated with a greater risk ofpoor neurologic outcome and death(144). Although there is general agree-ment regarding the importance of cardiaccomplications after aSAH, many aspectsof their pathophysiology, diagnosis, andtreatment remain undefined.

A widely held view postulates a se-quence of events involving acute cerebralinjury, derangements in autonomic func-tion, release of endogenous cat-echolamines, and activation of adrenergicreceptors, culminating in target organdamage (145). The severity of neurologiccompromise as measured by the Huntand Hess grade is highly predictive ofmyocardial necrosis after aSAH, support-ing the hypothesis that cardiac injury af-ter aSAH is a neurally mediated process(146). Significantly, impaired left ventric-ular function and low cardiac output el-evate the risk of cerebral ischemia andhave been identified as independent pre-dictors of symptomatic vasospasm (147).

Regarding diagnosis, several investi-gators have evaluated the significance ofcardiac-specific markers such as cardiactroponin I in patients after aSAH. In a7-day observation of 39 patients withaSAH, measurements of cardiac troponinI revealed a higher incidence of myocar-dial injury (21%) than predicted byCK-MB (13%), and elevations of cardiactroponin I were associated with a higher

incidence of congestive heart failure(148). Another group found that the sen-sitivity of cardiac troponin I in the detec-tion of echocardiographically demon-strated left ventricular dysfunction wassignificantly higher than CK-MB (100%compared with 29%) (149). In a thirdstudy, mild elevations in cardiac troponinI (�2.8 ng/mL) associated with depressedleft ventricular function in the absence ofsignificant electrocardiographic changeswere proposed as characteristics thatmight aid in the differentiation of neuro-genic stunned myocardium from myocar-dial infarction (150). Recently, there hasbeen increasing recognition of the impor-tance of BNP as a diagnostic and prog-nostic marker in patients with cardiacdysfunction. Increased serum levels ofBNP are highly predictive of the short-and long-term risk of cardiac deathacross the entire spectrum of acute cor-onary syndromes and in patients with de-compensated congestive heart failure(151). A correlation between increasedlevels of BNP and myocardial necrosis,pulmonary edema, and both systolic anddiastolic left ventricular dysfunction afteraSAH was demonstrated in a recent study(136). However, there is debate as to thesource—cardiac or cerebral—of BNP inpatients with aSAH (152). A recent studyevaluated serum and CSF levels of atrialnatriuretic peptide, BNP, and troponin Tin patients with aSAH. Of note, increasedlevels of atrial natriuretic peptide andBNP were detected in the serum but notCSF, leading to the conclusion that thesepeptides were exclusively of cardiac ori-gin (153). This contradicted previous re-sults in which a selective increase of BNP,but not atrial natriuretic peptide, sug-gested that the hormone was secreted inthe brain (134).

The therapeutic approach to patientswith cardiac dysfunction acquired in thesetting of aSAH is a matter of furthercontroversy. In light of the postulatedrole of catecholamines in the develop-ment of this disorder, early randomizedtrials evaluated the effect of pharmaco-logic � and � adrenergic receptor block-ade (e.g., phentolamine and propanolol)in patients with aSAH, noting a favorableeffect on the rate of myocardial necrosis,survival, and neurologic outcome (154,155). These data are at variance withmore recent studies that suggest thatneurogenically induced ventricular dys-function and its associated low cardiacoutput/pulmonary edema may exacerbatecerebral ischemia and should be treated

with the use of inotropic agents such asdobutamine (65, 147, 156). Finally, pa-tients presenting with severe neurocar-diomyopathy or cardiogenic shock andvasospasm may benefit from temporarysupport with IABC (108, 110).

Comment. Cardiac dysfunction com-plicating aSAH is common and has beenlinked to poor neurologic outcomes.These complications may contraindicate,or be exacerbated by, brain-targeted ther-apies such as hemodynamic augmenta-tion. Studies are needed to elucidate riskfactors, pathogeneses, natural history, di-agnostic markers, management strate-gies, and prognostic impact of these com-plications.

CONCLUSIONS

This review highlights some of thecontroversies that exist in the clinicalmanagement of patients with aSAH, asummary of which is presented in Table1, along with a classification of levels ofevidence (157, 158) in Table 2.

It is anticipated that these areas ofuncertainty will generate hypothesis-driven experimental and translational re-search, prospective observational studies,and clinical trials, with the goal of im-proving outcomes in these complex andchallenging patients.

ACKNOWLEDGMENT

We thank Tzipora Sofare, MA, for hereditorial assistance in preparing this ar-ticle.

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