Clinical Predictors and Management of Hemorrhagic Transformation

Current Treatment Options in NeurologyDOI 10.1007/s11940-012-0217-2

CRITICAL CARE NEUROLOGY (KN SHETH, SECTION EDITOR)

Clinical Predictors and Managementof Hemorrhagic TransformationRaphaella E. Weiser, MD1,*

Kevin N. Sheth, MD, FAHA2

Address*,1Department of Neurology, University of Maryland Medical Center, 22 SouthGreen Street, Baltimore, MD 21201, USAEmail: [email protected]: [email protected] of Neuro-Critical Care & Stroke, Neurology/Neurosurgery/EmergencyMed/Anesthesiology, University of Maryland School of Medicine, University ofMaryland Medical Center, R Adams Cowley Shock Trauma Center, Baltimore,USA

* Springer Science+Business Media New York 2013

Keywords Hemorrhagic transformation I Parenchymal hemorrhage I Hemorrhagic infarction I Thrombolytics ISymptomatic hemorrhage I Asymptomatic hemorrhage I Management of HT I Treatment I Clinical predictors IImaging I Ferritin I Blood pressure I Hyperglycemia

Opinion statement

Hemorrhagic Transformation (HT) has been well recognized as a common cause of hem-orrhage in ischemic stroke patients. Though this complication may occur independent-ly, it has been particularly dreaded in the post rTPA patient and thus has been the focusfor analysis of multiple thrombolytic trials. This review examines the effect of differentclinical predictors for hemorrhagic transformation and summarizes pertinent clinicaltrials, with a focus on the rational for design of future studies. Although currentlythere are no official guidelines for the acute management of HT per se, based uponreview of the literature regarding pertinent clinical predictors herein, an innovative ap-proach for the acute management of the HT patient is proposed.

IntroductionThere has been much debate on the epidemiology ofhemorrhagic transformation, partially because viewson the postulated mechanisms contributing to suchan entity have historically been split and thus contro-versy arose as to which population or pool of patientsshould be studied. In an analysis of anterior ischemicstroke patients who have not been subjected to throm-bolytic therapy, Terrusi et al., reported that the fre-quency of spontaneous HT was 12 % while the

frequency related to cardioembolic source was a bithigher at 18.9 % [1]. Studies which looked at posteriorcirculation stroke reported even a higher rate ofasymptomatic hemorrhagic transformation in the car-dioembolic population [2]. The epidemiological rateis further complicated by the fact that the incidencesand frequency of different stroke subtypes is multi-fac-torial and constitutes a combination of both environ-mental and genetic factors, both of which may vary

between different countries or customary diets. Studiesconducted in Italy for example, documented an overallrate of 9 % for HT [3] and noted that only 3 % ofpatients experienced the parenchymal subtype of HT,which was associated with increased morbidity or dis-ability.

In today’s era of thrombolytic therapy, HT hasgained even more of a central role in modern day dis-cussions of stroke complications. Numerous studieshave been conducted in an attempt of deciphering pre-dictors for HT, with the intent of impacting the overalltreatment and management of thrombolytic therapy.It is the hope of many that such studies will help wid-en the current TPA treatment window. While this hopemay still be in the horizon, clinicians who care for theacute and daily management of the HT patient mustfirst seek to attenuate those destructive processeswhich were shown to be clinical predictors of pooroutcome.

The goal of this review is to list several clinical pre-dictors of HT, as applied to all subtypes of ischemicstroke, both in the innate and post thrombolytic pa-tient, which can influence the daily management ofthe HT patient. In an attempt to further understandthe pathophysiology of HT, different mechanismsand postulated theories which shed more light onthe effect of such clinical predictors will be reviewed.In accord with the literature review, a proposal planfor the acute management of HT will be made. Lastbut not least, it is the intention and purpose that thisreview serves as a pivot for the rationale and need offuture clinical trials in the care of the HT patient.

Imaging as a predictor of hemorrhagictransformation (HT)Non Contrast Head CT reliably distinguishes ischemicfrom hemorrhagic stroke. However, its use as a predic-tor of hemorrhagic transformation is debatable. Whileearly studies reported a focal hypodensity on CT as anindependent predictor of hemorrhagic transformation(HT hereof) within the first five hours of stroke onset,[4] no consensus was reached on defining the bordersof such hypodensity. In the ECASS trial, which com-pared the incidence of HT between a placebo and atreatment group, the eligibility criteria for entering in-to the study was defined on CT as an area of ischemiawhich was less than one third of the MCA territory.Yet, these inclusion criteria were not deemed reliable[5]. The fact that large infarcts were excluded from

the ECASS trial was in accord with other studies whichdemonstrated infarct size as a predictor for hemor-rhage [6, 7]. In an attempt to better quantify infarctsize using CT, the Alberta Stroke Programme EarlyCT Score (ASPECTS) was designed and was found tohave a good inter-observer reliability [8]. Upon usingthe ASPECT score on data from ECASS II, a higher like-lihood of thrombolytic related parenchymal hemor-rhage was reported in patients with an ASPECTSscore less than or equal to seven [9] in essence validat-ing that an ASPECT score 97 corresponds well to lessthan one third MCA territory.

CT Angio has been utilized to predict hemorrhagictransformation as well. The clot burden score (CBS) as ameasure of contrast opacification, was shown to be asso-ciated with a lower ASPECT score as well as with a higherrate of parenchymal hematoma [10]. Using the ECASSdefinition for hemorrhagic transformation, it was foundthat patientswith lowerCBSwere significantlymore likelyto have parenchymal hematoma formation rather thanthe hemorrhagic infarction subtype of HT. The authorspostulated that a higher thrombus burden resulted in amore severe hypo-perfusion state and that thiswas predic-tive of HT, specifically of the parenchymal subtype.

TheMRI using aDWI sequencewas also employed inan attempt to characterize size/volume as a predictionfor HT. Looking at posterior infarcts, both infarct diam-eter and volume as measured by DWI were found tobe independent predictors which positively correlatedwith HT [11]. The size of a lesion on DWI was reportedas a predictive parameter of symptomatic hemorrhage al-so by Singer et al., who applied the ASPECTS score toDWI images in a study which predicted sICH risk afterthrombolytic therapy [12]. A combined volumetric anal-ysis tool which looked at the absolute volume of ische-mic tissue on DWI with ADC values below a specifiedcutoff has also been reported as a predictive measureto assess the risk for HT in the post TPA patient [13].

Regardless of which imaging modality was used,the pathophysiology behind the conclusion that largerinfarcts predispose to HT was attributed primarily tothe hypothesis that bigger infarcts involve a larger por-tion of the BBB and thus are more prone to cause hem-orrhage secondary to BBB rupture and ensuingreperfusion flow. Different imaging modalities andsequences were implemented in an attempt to betterquantify and predict BBB derangements, as describedherein. Contrast enhancement due to BBB disruptionand as a predictor of HT, was first reported using T1sequences. There appears to be two different types of


enhancements, vascular and parenchymal. In a retro-spective review of MRI patterns of patients with andwithout thrombolysis, early parenchymal hemorrhageduring the hyper acute stage was significantly associat-ed with symptomatic hemorrhagic conversion in postTPA patients while a predominantly vascular type ofenhancement was associated with an asymptomatichemorrhage and seen in the non TPA patient [14]. Fur-ther studies reported that early parenchymal enhance-ment as seen on post T1 contrast was found to bemore predictive of HT than DWI lesion volume orADC values [15]

The FLAIR sequence has been employed to charac-terize BBB permeability as well. Latour found the hy-perintense acute reperfusion marker (HARM) to bean early marker of BBB breakdown. The HARM is a hy-perintense signal observed on inversion recoveryimages after gadopentetate administration, and is be-lieved to be due to accumulation of contrast in CSFor ventricles before BBB breakdown. Lature foundHARM to be associated with HT and stroke severity[16]. Other patterns on FLAIR attributed to BBB dis-ruption include cortical enhancement of godolinumwhich is termed sulcal hyperintensity. Chau et al.,reported that such flair hyperintensity was predictiveof symptomatic hemorrhage after thrombolysis [17].Sulcal hyperintensity on FLAIR was also documentedafter intra arterial thrombolysis and found to be signif-icantly associated with HT. In this study, the possibil-ity that this hyperintensity was due to SAH wasnegated through a simultaneous T1 sequence in theacute stage which showed hyperintensity, contrary tothe known isointense/hypointense features of acuteblood on T1 sequence [18]. More recently, Campellet al., conducted a post hoc analysis of hyperintensitieson FLAIR sequences in the post tpa patient. After a lo-gistic regression analyzing various predictors, hereported that parenchymal hematoma type of HTwas poorly predicted by flair hyperintensity and in-stead was associated with age, baseline NIHSS, base-line DWI lesion volume and very low cerebral bloodvolume (VLCBV) [19].

The quests for further characterization of BBB dis-ruption led to numerous studies using perfusion imag-ing modalities. The theory was that permeabilityderangements vary in pattern and evolution untilreaching a state of hemorrhagic transformation. Assuch, imaging predictors of HT were sought after deriv-ing permeability images from a standard PWI source.Early evidence of BBB disruption on MRI was reported

by Latour [16]. Indeed, MR permeability studies wereutilized in an attempt to quantify defects in BBB.Looking at patients who did not undergo thromboly-sis, an association was found between such permeabil-ity parameters and hemorrhage. As such, the authorsproposed to use permeability rather than time fromonset as the key factor in decision making before ad-ministration of TPA [20]. In a prospective study, per-meabil i ty var iables extracted from T2 basedperfusion studies, specifically percent recovery andthe mean rR of the contrast agent, were shown to besignificantly greater in patients with subsequent HTwhen compared to those without [21]. On the otherhand, Bang reported that BBB permeability is a dy-namic process and that HT types may vary to the ex-t en t t h a t , i n some pa t i en t s , p e rmeab i l i t yderangement may not be accompanied by HT [22].This query was addressed further by, Kim et al., whostudied whether the pretreatment perfusion status con-tributed more or less than the tissue status (as mea-sured by size of DWI lesions) to the development ofHT as measured via gradient echo imaging. Theauthors found that severe perfusion delay was an inde-pendent predictor of HT regardless of DWI lesion vol-ume or CT changes. Thus, perfusion imaging can helpidentify an “at risk patient “even if his CT or DWI im-aging seems innocuous. The study recertified the pre-cedent finding, i.e., that there was poor correlationbetween radiological and clinical categories of HT.Therefore, HT with severe hypo perfusion may stillbe asymptomatic due to apparently nonimpressive tis-sue status, regardless of the volume or type of HT seenon imaging and may result with very little impact onstroke outcome [23]. The apparent controversy inthese preliminary studies led to the conducting oftwo prospective multicenter studies termed DEFUSEand EPITHET which utilized MRI to predict hemor-rhage after TPA administration. In both studies, TPAtreatment was given and an MRI was performed beforeand after this treatment.

The diffusion and perfusion imaging for under-standing stroke evolution (DEFUSE) trial looked at se-verity of perfusion delay and DWI lesion volume in anattempt to identify risk factors for HT after recanaliza-tion therapy. In this prospective study, MR perfusionwas obtained immediately before and 3–6 h aftertreatment with TPA. No conclusions were drawn onthe efficacy of TPA since there was no placebo controlgroup and the trial involved only one arm. However,repercussions were drawn on the use of PWI and

Clinical Predictors and Management of Hemorrhagic Transformation Weiser and Sheth

DWI for prediction of successful reperfusion. The goalwas to target the ischemic penumbra at risk of infarc-tion and the relationship between the ischemic andinfracted tissue was classified into different categories.A DWI lesion volume more than 100 ml was associat-ed with poor outcome and defined as a “malignantprofile” while a “mismatch profile” was defined by aPWI lesion 1.2 times larger than the DWI lesion. Itwas reported that reperfusion had an increased oddsof achieving a favorable response in the “mismatchprofile” and specifically within the subtype of “targetmismatch profile” [24]. The “no mismatch” profiledid not benefit from early reperfusion and the “malig-nant profile” was associated with fatal intracranialhemorrhage after reperfusion. In a secondary sub-study of the DEFUSE data, clinical outcome measureswere evaluated at both the 30d and 90d endpoint aftertreatment, using three different outcome scales (Ran-kin, NIHSS and Barthel). Again, a strong associationbetween early reperfusion and clinical response wasseen in the PWI/DWI mismatch group. Furthermore,the NIHSS score of 0–2 was found to be the best dis-criminator of clinical response and a powerful mea-sure of t reatment e f fec t [25] . A l though theEchoplanar Imaging Thrombolytic Evaluation Trial(EPITHET) used the same mismatch definitions asthe DEFUSE study, the prevalence of the mismatchprofile was higher in the EPITHET study (86 % vs.54 % in diffuse) and the study itself had two arms,treated and placebo, which were double blinded. TheEPITHET study showed that patients with a malignantprofile had a worse clinical outcome when treatedwith alteplase. However, unlike the DEFUSE study,such patients were not found to have an increased riskfor symptomatic ICH when defined by the SITS-MOSTdefinition which is limited to parenchymal type ofhemorrhage [26].

CT perfusion may allow for a more rapid view ofpenumbral imaging. The ischemic penumbra is esti-mated on CT perfusion by looking at regions with nor-mal CBV and decreased CBF. A study which comparedCT and MR was found in agreement when using theinclusion criteria for mismatch as listed in the DEFUSEtrial [27]. Indeed, on closer analysis, most of the dis-agreements between CT and MR perfusion imagingwere due to insufficient coverage with CTP whichrestricts the proper estimation of mismatch. Similarly,Souza LC reported that admission CT perfusion pre-dicts HT with similar accuracy to DWI [28]. A study us-ing CT perfusion assessed the malignant profile as

defined by the DEFUSE study and reported that it cor-related with poor outcome after TPA therapy when giv-en by the current timeline protocol [29] and, therefore,can be used interchangeably with MR perfusion. In aprospective study, prediction of HT was evaluated withCT perfusion by comparing permeability surface areaproduction maps (PS) between HT and non-HTgroups. It was found that patients with HT had a sig-nificant higher PS than those with acute stroke butwithout HT. Furthermore, although patients treatedwith TPA were more likely to have HT, no significantdifference was found in PS between the tpa and thenon-tpa group [30]. In a retrospective study evaluating32 patients, admission BBB permeability which wascalculated by perfusion CT was found to be 100 %sensitive and 79 % specific in predicting symptomaticHT and malignant edema (ME) [31] although thestudy was limited by very small sample size with onlysix patients eventually developing either SHT or ME.Given all these positive predictors, a pilot trial has be-gun to emerge in the hope of using perfusion studiesto widen the tpa window. In a prospective case controlstudy, patients with acute ischemic stroke received in-travenous TPA beyond the 4.5 h window using specificperfusion CT criteria. Although the authors reportedthat delayed thrombolysis was associated with a worseclinical course, still they found that the primary safetyand efficacy endpoints were comparable between theearly and delayed thrombolysis group thus justifyinga future clinical trial to test the safety and efficacy ofperfusion CT guided iv tpa after a 4.5 h window [32].

Besides disruptions of the BBB, other proposed eti-ologies emerged in the quest for radiological predic-tors of HT using imaging modalities. Of specialinterest, silent cerebral micro bleeds (CMB) as visual-ized on T2weighted GRE, have been profuselyreported in the literature as possible predictivemarkers for HT. Studies looking at detection of micro-bleeds using T2 sequences hypothesized that a severepreexisting microangiopathy, predisposes towardshemorrhage by causing weakening of vessel wallsand subsequent extravasation of plasma and bloodcells into brain parenchyma potentially yielding HT.These “silent microbleeds” are visualized on T2weighted GRE and EPI –SWI sequences and are a prod-uct of hemosiderin laden macrophages adjacent tosmall vessels. Their occurrence was reported as a mark-er for risk of HT in patients receiving TPA [33]. A casereport demonstrated that such preexisting microangi-opathy may be limited to one location within the


brain parenchyma and intact elsewhere within the pa-renchyma of the same patient [34]. It was postulatedthat this microangiopathy was secondary to hyperten-sion/ amyloidosis/ prior ischemic injury. However, ina recent review of the literature, hypertension was notfound to be consistently associated with cerebralmicrobleeds or with other MRI findings characteristicof chronic HTN. Instead, such cerebral microbleedswere linked to age, Asian ethnicity, leukoaraiosis andCAA [35] while the HTN factor was reported to requirefurther analysis. Still, concerns were raised about thesafety of thrombolysis in patients exhibiting such si-lent microbleeds. A retrospective chart analysis foundthat stroke patients with small number of microbleedson MR could be safely treated with thrombolysis [36].More recently, the BRASIL study, which was a multi-center retrospective analysis of the bleeding risk instroke imaging before thrombolysis, concluded thatthe risk estimate of hemorrhage in CMB is unlikelyto exceed the benefit of thrombolytic therapy. Yet,conclusions about the rare case of a patient with mul-tiple CMBs could not be made and the necessity for aprospective trial to assess prognosis was warranted[37].

Hypoperfusion was also reported as an etiology forHT and investigated by looking at signal changes with-in venous structures. Specifically, using a T2 gradientecho sequence, strong correlation was reported be-tween abnormal visibility of transcerebral veins(AVV) and subsequent occurrence of HT in the postTPA patient [38]. The fact that no findings were foundon a corresponding CT, lead the authors to concludethat MRI allows better patient selection and that theuse of TPA should be considered with extreme cautionin patient with obvious AVV.

Ferritin as a predictor of hemorrhagictransformationIt is well known that iron plays a role in both initiatingand propagating lipid peroxidation, thus causing inju-ry to cell membrane resulting in edema and eventuallycell death. The mechanism is related to the fact that af-ter ischemic injury, oxygen superoxide radicals releaseiron from ferritin and thereby iron in itself acts as apro-oxidant cofactor causing increased production offree radicals and thus propagating atherosclerosisand lipid peroxidation eventually leading to edemaand lysis of the cell membrane. Indeed, in experimen-tal models iron chelating agents were shown to reducebrain edema induced by reperfusion after ischemia

[39]. In the brain, most of the iron which is not boundto heme is stored as ferritin in both astrocytes andmicroglia. Yet the serum concentration of ferritin isproportional to tissue iron stores and in the absenceof inflammation, malignancy or infectious diseases,it can be used to estimate the tissue iron stores.

Since ferritin is also an acute phase reactant, it maybe speculative at first to assess whether or not a rise inferritin is a cause or an effect of the triggering responseas seen after ischemic stroke. This was addressed in astudy conducted by Erdemoglu [40] in which fifty-one patients with acute stroke were followed within24 h of symptom onset. Admission levels of both se-rum ferritin and cortisol were measured and clinicalstatus was evaluated on both admission and day 21.No correlation was found between serum cortisoland ferritin, thus negating the idea that a stressful re-sponse induces the rise of ferritin levels. The authorsfound that the serum ferritin level was higher inpatients with large lesion size, and that the two wereindependently associated with mortality. Ferritin wasalso correlated with the severity of stroke as evaluatedby neurological status in admission and clinical followup. Yet the study above included both ischemia andhemorrhage stroke subtypes in its analysis. In a morerecent study, the role of ferritin specifically as a predic-tor of hemorrhagic transformation in acute ischemicstroke was evaluated. Using a prospective study designwhich analyzed patients who presented with ischemicstroke within 24 h, HT was classified according toECASS classification into hemorrhagic infarction (type1 and 2), and parenchymal hematoma ( type 1 and 2)as well as into asymptomatic, and minor/major symp-tomatic HT based on NIHSS. The ferritin level wasfound higher in patients who developed HT, and espe-cially PH and sHT. After adjustment was made for con-founding variables, serum ferritin was found to beindependently associated with sHT (symptomaticHT), and a more severe HT ECASS grade was shownto be associated with a higher ferritin level. The cutofflevel of ferritin above which HT was predicted wasrecorded as 144.8 (sensitivity and specificity of74 %). Yet, the serum level with the highest sensitivityfor HT prediction was 171.8 (specificity 77 %). Theauthors therefore concluded that lowering ferritin levelwith iron modifying agents or using free radical scav-engers could help prevent HT of ischemic stroke andthat patients who present with increased ferritin con-centrations should be carefully managed prior toreperfusion therapy or anticoagulants [41••].


Although the study above attempted to excludepatients with infectious disease on admission, theauthors appropriately admit that the relationship be-tween ferritin and HT may have been confounded byinflammation. And yet, it has been reported that whenlooking specifically at serum ferritin iron, correlationswith iron stores are possible even in the presence of in-flammation [42].

Furthermore, it would also be interesting to designa study which analyzes the ferritin level in the cerebro-spinal fluid since serum ferritin in the CSF was foundto be elevated in various disease which impair the BBB[43, 44]. In summary, while a more thorough prospec-tive study is called for, and although no specific offi-cial guidelines exist at present, in light of numerousthrombolytic studies which reported poor associationwith elevated iron stores[45, 46] it would be pertinentto lower ferritin level/ use iron chelators in the acutemanagement of the HT patient.

Body temperature as a predictor of hemorrhagictransformationHypothermia has been shown to limit ischemic dam-age by decreasing metabolism, reducing inflamma-tion, suppressing breakdown of the BBB andpreventing free radical formation. Several studies inhumans showed that pyrexia after stroke onset islinked to increased morbidity and mortality [47, 48].In a post hoc analysis of a prospective study, a sub-group of patients who have not received TPA andwho have not had concomitant inflammatory or infec-tious disease, were isolated and followed for HT asclassified by the ECASS II criteria [49••]. It was foundthat after adjustment for cardio embolic stroke sub-type, NIHSS score, diastolic blood pressure and DWIlesion volume on admission (all of which were some-what associated with HT), body temperature was stillindependently associated with HT. In particular, themean temperature in the first 24 h was higher inpatients with parenchymal hemorrhage. Furthermore,again looking at the first 24 h window, a higher tem-perature was correlated with a higher severity of HT. Itis of special interest to find that while statistical signif-icance with a p value G0.0001 was reached, the actualdifference in temperature between patients with andwithout HT was very small, only 0.05 degree Celsius.Thus, in practice, a significant difference can be madeusing a temperature goal of 36.5 (as reported in thisstudy) without any complicated interventions.

Looking at patients who had undergone thrombo-lytic therapy, a higher body temperature at 24 h, butnot at baseline, was associated with symptomatic HTand poor outcome, as well as to greater hypodensityvolume and lack of recanalization [50]. The cutofftemperature reported was9or equal to 37 degrees Cel-sius, again not too far from normal body temperature.In light of these findings, for the acute management ofthe HT patient, it would be pertinent to actively pursuesuch mildly lowered but highly effective temperaturegoal. Active measures include cooling blankets, chilledsaline or advanced cooling devices such as endovascu-lar catheters which allow a quicker reduction of wholebody temperature [51]. Recently, an approach wasproposed for selective brain cooling via local intra ar-terial perfusion with cold saline [52] . Such an ap-proach bypasses the side effects of whole bodyhypothermia and was reported to allow hypothermiato be reached within ten minutes of initiation of theinfusion.

Anti-platelets as a predictor of sICHStudies investigating baseline antiplatelet use as a pre-dictor for hemorrhagic transformations, have dividedoutcomes in the literature. On the one hand, aspirinwas not related to the risk of severe HT in the NINDStrial [53]. Other studies also did not find a significantassociation with prior antiplatelet and sICH [54–56].The Multicenter TPA stroke survey reported that pre-treatment with aspirin was associated with a risk ofsICH in univariate analysis but not when examinedunder multivariate analysis. Furthermore, althoughlow platelets were associated with a higher rate ofICH, only antiplatelets other than aspirin (mainlyticlopidine) were at high risk for symptomatic ICHor PH using a model that included only clinical varia-bles. Yet even this association was lost, when lookingat a model that also incorporated laboratory and CTfindings. Since the number of patients on antiplateletsother than aspirin was small, the authors concludedthat such findings should be interpreted with caution[57]. On the other hand, the ECASS II study [58]showed a higher incidence of PH and sICH in TPAtreated patients who had used aspirin before stroke.Specifically, sICH occurred in 18.9 % of TPA treatedpatients who were already on aspirin, compared to on-ly 6.2 % in patients who were not on aspirin. Thisfinding is aligned with results from the multicenteracute stroke trial Italy (MAST –I) which comparedstreptokinase vs. control, six hours after stroke onset,


as combined with current aspirin use. It was foundthat, looking at the streptokinase group which was al-so given aspirin, there was a significantly increasedmortality from all causes including intracranial hem-orrhage as diagnosed on CT or autopsy.

Still, other studies conclude that although antipla-telets were associated with increased risk of sICH,overall the outcome is still favorable [59]. The rationalfor the beneficial effect is attributed to the fact that as-pirin remains biologically active for four to six daysand, thus, may prevent early re-occlusion after TPAtreatment. Similarly, looking at the SAINT 1 and 2 tri-als, Cucchiara [60] reported a significant relationshipbetween baseline antiplatelet use (especially doubleantiplatelet therapy) and the risk of sICH. Howeverdespite the risk of sICH, defined as hemorrhageaccompanied by an NIHSS 9 or 0 to four, the finalclinical outcome was not altered and; hence, recom-mendations to provide thrombolysis to antiplateletusers remained in effect. Of note, the theory of aspirinuse as an agent instrumental in decreasing recanaliza-tion rate was recently investigated in a prospective tri-al. The Antiplatelet therapy in combination with rTPAThrombolysis in Ischemic Stroke (ARTIS) trial wasdesigned with a rationale that concomitant use of as-pirin will decrease recanalization rate. However, thetrial was forced to come to a halt prematurely sec-ondary to increased incidences of sICH in the aspi-rin treated arm. The published results, therefore,did not change the current guidelines, i.e., initiationof antiplatelets therapy only 24 h after alteplaseadministration.

Looking at dual antiplatelet use, upon analysis ofthe SITS database [61], Mayaza et al., reported thatof the nine factors listed as clinical predictors, dualantiplatelet use, that is, use of both aspirin and clopi-dogrel, was the strongest predictor for sICH. Doubleantiplatelet therapy was previously correlated with in-creased bleeding complication in stroke prevention tri-als [62, 63]. However, in an analysis of the Safeimplementation of treatment in a stroke internationalregistry (SITS-ISTS), Diedler et al., compared the risk ofpatients receiving one or two antiplatelets (aspirin,clopidogrel, dipyridamole ) at baseline with symp-tomatic ICH outcome as measured both by the SITS-MOST (deterioration on NIHSS greater than or equalto four plus ICH type 2 within 24 h) and ECASS def-inition (NIHSS deterioration greater than or equal to 4plus any ICH). Although the combination of aspirinand clopidogrel was indeed associated with increased

risk of sICH per ECASS II criteria (OR 2.11, 95 %CI), no increased risk for mortality or poor functionaloutcome was found to be significant regardless ofwhich sICH definition was used or which antiplateletssubgroup was investigated. The authors concludedthat the excess of sICH was small compared with thebenefit of thrombolysis and; therefore, that thrombol-ysis should not be contraindicated in patients on APtreatment [64].

Blood pressure as a predictor of hemorrhagictransformationThere is a controversy in the literature as to the desir-able role of blood pressure. On one hand, elevatedblood pressure increases the risk of cerebral edemaand HT, but on the other hand, it preserves perfusionof the ischemic penumbra. Similarly, low blood pres-sure can increase infarct size and yet is desirable whenedema is present. The risk of hemorrhagic transforma-tion from uncontrolled severe hypertension has notbeen well quantified simply because such patientswere excluded from all stroke thrombolysis trialsand, furthermore ,current guidelines for TPA adminis-tration necessitate controlling the blood pressure priorto using the AHA/ASA parameters of systolic BP(G185mmHG) and diastolic (G110mmHG) [65].

However, in a secondary analysis of the NINDS tri-al, the antihypertensive therapy in the placebo groupwas not associated with a less favorable outcome atthree months while antihypertensive therapy in theTPA treated group seemed to worsen outcome andwas associated with symptomatic hemorrhage. How-ever, antihypertensive therapy used in the nINDS trialwas modest in effect, administered in a nonrandom-ized way and the analysis overall was post hoc usinga small sample size [66]. Both the MAST E [67] andECASS II [58] study reported that higher baseline sys-tolic blood pressure was associated with HT. Lookingat the SITS-MOST registry, systolic BP was reportedas a predictor for symptomatic HT [68] and a second-ary analysis showed that, upon dichotomizing base-line systolic blood pressure, a systolic level of 146was found to be optimal for maximizing the risk dif-ference [61]. And yet, in the CASES study, after adjust-ment for baseline NIHSS score, age, baseline serumglucose level and baseline ASPECTS score, a trend topoorer outcome persisted among patients whoseblood pressure was lowered before thrombolysis.Thus, lowering of blood pressure did not protectagainst, nor increase the risk of, symptomatic intracra-


nial hemorrhage [69]. It appears, therefore, that the in-fluence of blood pressure may have a temporal courserather than a fixed value.

Indeed, Dawson et al. [70] showed that autoregula-tion of blood pressure is impaired in ischemic braintissue. As such, it is likely that sharp rises and falls inblood pressure, even if only minor, can exacerbate ce-rebral perfusion defects and may result in rupturedvessels and subsequent hemorrhage [71]. In a retro-spective analysis of systolic BP variability, using datafrom the ECASS II trial [72], Young et al., reported thata parenchymal hemorrhage subtype of HT within thefirst seven days of ischemic stroke was independentlyassociated with the dynamics of systolic BP as mea-sured by different parameters including mean, succes-sive variation, maximum and minimum in the first24 h after thrombolysis. Similar associations werenot found in the placebo group. The authors conclud-ed that continuous blood pressure monitoring is es-sential for prognosis in the thrombolytic patient.Similarly [73] Delgado reported that blood pressurevariability is associated with greater diffusion-weight-ed imaging lesion growth and worse clinical coursein patients with stroke treated with IV tissue plasmin-ogen activator. However, he stated that the impactvaries depending on the occurrence of early recanaliza-tion after thrombolysis.

In an analysis of the Echoplana Imaging Thrombo-lytic Evaluation Trial (EPITHET) study, looking specif-ically at the 24 h post thrombolytic treatment, Butcheret al. [74] reported that parenchymal hemorrhage(group as PH1 plus PH2) was associated with a higheraverage SBP/DBP and MAP. Specifically, for every10 mm Hg weighted average elevation in BP in thepost treatment period, the odds of PH increased by59 %. Furthermore, these BP elevations were most ev-idently seen six hours after treatment, the window oftime most consistent with hypertension secondary toelevated intracranial pressure subsequent to hemor-rhage [75]. Indeed, this relationship between HT andBP variability was further explored by Ko [76••] usingthe Korean stroke registry along with the ECASS II def-inition of HT subtypes. After defining blood pressurevariability as the square root of the summative averagedifference in BP between successive measurementsduring the first 72 h, it was shown that variabilityparameters for both systolic and diastolic BP were as-sociated with HT across grouped quartiles of mean BP.The variability factor, therefore, was not limited to theextreme mean BP measurements. Unlike the study by

Young, this association between these BP parametersand HT was independently seen even in the groupwhich was not administered thrombolysis.

Age as a predictor of hemorrhagic transformationStudies examining the effects of age on the risk of ICHafter t-PA have inconsistent results. Indeed, it is wellrecognized that small vessel white matter changes in-crease with age and vascular risk factors [77, 78]. Inparticular, cerebral amyloid angiopathy has beenshown to predispose towards symptomatic hemor-rhage [79]. Furthermore, some studies suggest a trendtowards increased HT with leukoaraiosis [80, 81].

However, although advanced age has beenreported as a risk factor for ICH in controlled throm-bolysis trials for MI [82, 83], this fact was not convinc-ing when looking at thrombolysis trials for stroke.

The analysis of advanced age as a predictor for ICHis particularly limited in patients over the age of 80,simply because many studies (including the ECASSand ATLANTIS) excluded patients beyond that age,while other studies such as MAST I 1995, MAST E1996 and NINDS 1995 simply did not have a specifiedupper age limit. Upon attempt to analyze the age fac-tor in the NINDS trial, for example, only 42 patients(7 %) over 80 years old were recruited and includedin the study. In a subgroup analysis of this trial, therewas a significant association of age with an increasedrisk of sICH in univariate analysis, but the associationwas no longer significant after multivariable model-ing, perhaps secondary to a small sample of sICHand lack of power. Furthermore, the more subtle typeof HT, i.e., HI rather than PH, was prevalent in theNINDS study [53]. Looking at ECASS II, Laruuereported that increased age as categorized by decadesup to the age of 80 was associated with parenchymalhemorrhage (OR, 1.3; 95 % CI, 1.0 to 1.7) but notHI after TPA, Still, the distribution of parenchymalhemorrhage by decade did not show a clear cutoff val-ue [58]. On the other hand, in a multivariate analysisof the combined data from NINDS, ECASS and AT-LANTIS trials, age was reported to be an independentrisk factor for sICH, defined as substantial parenchy-mal hematoma. This may be secondary to increasedcombined sample size, but such combination of trialsis also limited by differences in trial methodologies,and definitions of outcome variables, all of whichmay affect overall analysis of results [84].

The Canadian trial reported that age over 80 wasnot a risk factor for symptomatic intracranial hemor-


rhage [85]. Regarding the SITS study, Mayaza et al.,reported that the sharpest increase in risk for sICHoccurs in the beginning of the eighth decade, withthe age of 72 reported as the cutoff between lowerand higher risk groups [61]. However, in a more de-tailed review of the SITS registry, although patientsolder than eighty had more severe stroke, upon adjust-ment of other risk factors there was not an increasedrate of symptomatic intracerebral hemorrhage in those980 years of age [86].

Although an age greater than 80 was an exclusioncriterion from the ECASS 3 trial, results of which ex-panded the time window to 4.5 h, there have beenmultiple studies re-evaluating the need for this criteri-on. Cronin et al. [87••] reported, using analysis fromGet With Guidelines Database, that age 980 was notassociated with increased risk of sICH. Other studiesconferred similar results [88, 89] and some reportedno association even in patients older than 85 [90].

Hyperglycemia as a Predictor of HemorrhagicTransformationSeveral multicenter trails have addressed hyperglyce-mia as a clinical predictor for hemorrhagic transforma-tion. An initial analysis of the NINDS trial failed tofind an association between admission hyperglycemiadefined as glucose 9300 mg/dl, and sICH within 36 hand reported that only stroke severity as defined by theNIHSS and CT changes are independent predictors ofsymptomatic hemorrhage. However, a re-analysis ofthe data which incorporated placebo treated patientsand thus increased the sample size, did show thatthe odds of sICH increased by 1.75 for every100 mg/dl increase in initial blood glucose. Further-more, it showed that there was an inverse correlationbetween hyperglycemia and neurological improve-ment. This association was independent of stroke se-verity, history of diabetes and of the treatment arm.[91]. Similarly, looking at the TOAST trial, hyperglyce-mia was seen to be a worse outcome in non-lacunarstroke. Although no association was found with hem-orrhagic transformation, the association between hy-perglycemia and a worse outcome was independentof diabetes [92]. The multicenter TPA stroke surveygroup [93] also showed an independent associationbetween higher glucose levels and ICH after TPA.

Looking at the ECASS II study, blood glucose atbaseline was not reported as a significant risk factorfor PH in Larrue’s analysis of the ECASS II trial. How-ever, a more recent analysis showed that the relation-

ship actually depends on the timing of glucosemeasurements. Using the European cooperative acutestroke study (ECASS-II), database, Young et al., lookedat associations between admission and 24 h glucoselevels with neurological outcome [94]. Hyperglycemiawas defined as glucose level 9140 mg/dl, and the ad-mission level was taken within six hours of stroke on-set. Twenty four hours later this level was repeated andhence four different patterns of serum glucose wereobtained. Neurological outcomes measured includedNIHSS at 7 days ( of which improvement was definedas a four point decrease from baseline NIHSS), a Bar-thel index at thirty days, a Rankin scale at ninety days,mortality at 90 days and hemorrhagic transformationwith the first seven days, as distinguished accordingto the ECASS-II criteria (Young [18]) HI, HI2, PH,PH2. The authors found that of the four subgroups,persistent hyperglycemia which was defined as hyper-glycemia both at admission and at 24 h was the high-est risk group among non-diabetics. This subgroup ofpersistent hyperglycemia was shown to be inversely as-sociated with neurological improvement at seven days,or with a favorable outcome at 30/90 days, as well di-rectly associated with parenchymal hemorrhage ( OR06.64, 95 % CI ).The fact that parenchymal hemorrhagewas reported to be much more prevalent than hemor-rhagic infarction in the persistent hyperglycemia pop-ulation leans against a natural reperfusion process. Asdescribed previously, [95] the different subtypes of HTdefined by the ECASS II trial were traced to differentpathogenesis and it was the parenchymal subtype ofhemorrhage which was directly related to the effectsof TPA while HI was regarded as a natural process ofischemic damage and reperfusion. According toYoung et al., delayed hyperglycemia that is, hypergly-cemia solely at 24 h, was also associated with paren-chymal hemorrhage and with increased likelihood ofdependency at three months. However, the subgroupof acute and transient hyperglycemia at baseline didnot demonstrate any correlation with worse outcomeat the various endpoints measured. A similar studyby Baird et al., showed that persistent hyperglycemiaas measured via serial glucose monitoring contributedto higher mean glucose and unlike baseline glucoselevel, was found to be an independent determinantof infarct expansion and associated with worse func-tional outcome [96].

In the sub-analysis of the diabetic population ofpatients, no significant associations were found be-tween hyperglycemia and stroke outcome. This finding


is in accord with Bruno’s analysis of the NINDS trialabove. In fact, Young et al., demonstrated that the as-sociation between hyperglycemia and parenchymalICH is strongest in nondiabetic patients in which hy-perglycemia is present at 24 h, with or without base-line hyperglycemia, while patients with elevatedbaseline glucose did not show an increased risk of pa-renchymal hemorrhage. Although the prognostic utili-ty of hyperglycemia, speci f ical ly in the postthrombolysis group, could not be commented uponsince the study analyzed the thrombolyzed and non-thrombolyzed patients together, the study still raisesquestions on the fact that a history of diabetes was ex-cluded from the ECASS III study. Similarly, looking atthe Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy (SITS-MOST), Mazya [61] reportedthat elevated blood glucose level910 mmol/l was in-dependently associated with sICH, but that such asso-ciation was not seen in patients with known diabetesmellitus and baseline glucose levels G10 mmol/L.The lack of a strong link between a history of diabetesand the effects of hyperglycemia was also seen uponanalysis of the Safe Implementation of Treatments inStroke International Stroke Thrombolysis Register(SITS-ISTR) [97]. In this study, the association be-tween admission blood glucose was divided into sev-en categories and the outcome was reported asmortality, independence at three months and symp-tomatic intracerebral hemorrhage. Looking at glucoseas a continuous variable, associations of clinical signif-icance were found with higher mortality, lower inde-pendence, and increased risk of SICH. Looking atglucose as a categorical variable, levels 9120 were asso-ciated with higher odds for mortality and lower oddsfor independence, and levels between 181 and 200md/dl were associated with increased risk of SICH.Still, such association trends were also seen in patientswithout a history of diabetes. Furthermore, afteradjusting for baseline imbalances the authors didnot find a significant difference in SICH rates betweenpatients with and without a history of diabetes, and infact the association of hyperglycemia with poor out-come was stronger than that with a history of diabetes.Following the same trend, in a multivariable analysisof the Canadian alteplase stroke effectiveness study,hyperglycemia was one of only two variables whichwere reported as independent predictors of symptom-atic intracranial hemorrhage [69]. In a subanalysis ofthe CASES trial, Poppe reported that admission hyper-glycemia was independently associated with increased

risk of sICH and unfavorable outcome at 90 days [98].Yet this observation, again, was true for patients withand without a history of diabetes.

The fact that a history of diabetes does not accu-rately predict a risk of hemorrhagic transformation rai-ses queries as to whether the effect of glucose ischronic or acute. Although perfusion mechanismsare related to the pathophysiology and repercussionsof hyperglycemia [99] an increased risk of hemorrhag-ic transformation following an ischemic insult was al-so reported immediately after inducing hyperglycemiain rats when compared to controls [100]. These reper-fusion abnormalities are attributed to endotheliumdamage, increased expression of adhesion molecules,as well as to glycosylation of vasodilating protein orantithrombic substances such as nitric oxide [101].Hyperglycemia causes glycosylation of proteins, lipidsand nucleic acids resulting in advanced glycation endproducts (AGE) via oxidative, radical generating reac-tions. Indeed, receptors for AGE are located in manytissues including CNS and arteriolar endothelial cells.Yet it is not only chronic hyperglycemia which subse-quentially generates oxygen free radicals; it was shownthat AGE products can form also after brief episodes ofhyperglycemia[102] thus not necessitating a history ofdiabetes to be present.

There are other explanations for the etiology ofacute hyperglycemia serving as an agent for hemor-rhagic transformation in the non-diabetic patients.First, hyperglycemia may result from an acute stress re-sponse via activation of the hypothalamic-pituitary-adrenal axis, resulting in a rise of cortisol and catechol-amines. Such systemic response has been correlatedwith underlying stroke severity, and was previouslyreported as a plausible mechanism for elevated glu-cose levels after cerebral ischemia by Capes SE [103]and Tracey F, Stroke 1994; 25 424. Indeed, lookingat the non-diabetic patient Cape et al., reported athreefold increase in mortality with post stroke hyper-glycemia.

Elevated serum glucose may also be a reflection ofundiagnosed diabetes or more commonly of impairedglucose tolerance [104]. Indeed, hyperglycemia wasshown to be an independent predictor of stroke out-come [105]. Another plausible theory is that acute hy-perglycemia results from direct injury or irritation ofbrain areas involved in glucose regulation, an etiologysupported by the association of hyperglycemia withstrokes involving the insula [106]. Whichever thecause for the acute rise in glucose may be, its deleteri-


ous effect on the ischemic brain is well documented,including cellular acidosis caused by anaerobic glycol-ysis, enhanced free radical production, increasedblood–brain barrier permeability, impaired mitochon-drial function, influx of intracellular Ca2+, and cellularedema [107]. In particular, glucose is instrumental inproducing NADPH via the pentose phosphate path-way, and when it reacts with oxygen, superoxideforms. In fact, blocking NADPH oxidase with apocy-nin was shown to result in decreased BBB permeabilityand smaller hemorrhagic volume in hyperglycemicrats [108, 109]. The resulting oxidative stress can sub-sequentially activate the inflammatory cascade to con-tinue and promote tissue injury [110]. Such activationof the prostaglandin pathways produce vascular pa-thology and influence the elasticity of vessels and vas-cular tone, both of which affects reperfusion orpredispose to hemorrhage.

Looking at preclinical and clinical data, while it wasvalidated that chronic hyperglycemia directly affectsblood vessels and influences collateral circulationthrough accelerated atherosclerosis, tissue injury was al-so documented after only a short term of experimentalhyperglycemia [111]. Indeed, metabolic changes wereshown to produce direct tissue injury as demonstratedin several studies. Gisselsson et al. [112] showed that in-fusion of glucose in the peri-ischemic period contributedto increased infract size despite being discontinued be-fore reperfusion. This suggested that normalizing glu-

cose levels without exogenous insulin was notsufficient to reverse the effects of hyperglycemia. The roleof exogenous insulin was investigated using the UKGlu-cose Insulin in Stroke trial (GIST-UK). Although this trialwas stopped prematurely due to slow enrollment, nodif-ference in clinical outcome was seen between the twoarms of insulin vs. saline infusion. However, this findingmay be related to the late initiation of therapy (median14 h after stroke) and the modest reduction in glucoseachieved in the treatment arm (0.57mmol/l) [113]. Cur-rently, the Stroke Hyperglycemia Insulin Network Ef-fort (SHINE) study was launched as a phase threesingle blinded randomized control trial comparingmore intensive glucose control with standard ofcare glucose control in hyperglycemic ischemicstroke patients. The primary objective of this studywas to determine the efficacy of tight glucose con-trol to a target range of 80-130 mg/dL with IV in-sulin infusion, vs. the standard care SC insulinsliding scale with a target ofGor equal to 180.The trial was designed to look at the effect of hy-perglycemia within 12 h of stroke symptom onset,and results will shed more light on the role of in-sulin in reducing the risk of hemorrhagic transfor-mation in both the diabetic and nondiabeticpopulation [114••]. Still, more advanced researchis currently taking place in an effort to incorporateother agents towards the goal of mitigating the del-eterious side effects of hemorrhagic transformation.

Treatments of the future

With the growing acceptance of thrombolytic therapy for acute stroke, andthe recognition that, although TPA is a clot dissolving agent, it can also resultin cell damage, numerous pharmacological interventions have been pro-posed in an effort to prevent the subsequent reperfusion injury which causesendothelial cell damage, increased edema and cell matrix damage, all ofwhich pave the way to HT [115]. Such interventions target enzymes involvedin membrane remodeling [116], the inflammatory and oxidative stress re-sponse [117], as well as agents that halt accumulation of free radicals [118].Free radical spin trap compounds for example, such as pheny N- t- butylni-trone (PBN), has been shown to reduce HI in rat collagenase and embolismmodels [119]. It was also demonstrated to be a potent scavenger of freeradicals at the blood endothelial cell interface [120].

Matrix membrane metalloproteinase (MMP) are instrumental in mem-brane remodeling and production of cytokines that damage neurons andvasculature [121]. Specifically, MMPs were shown to play an instrumental


role in forming active TNF which subsequentially damages micro vessels andbrain tissue [122] thereby promoting brain edema and hemorrhage. It hasbeen previously reported that TPA exerts direct effects on various brain cellsand specifically up regulates extracellular proteases from the matrix metal-loproteinase family (MMP). The MMP are known to be upregulated earlyafter cerebral ischemia and are instrumental in disrupting the BBB bydegrading inter-endothelial tight junction proteins, basal lamina proteins,and consequentially promoting edema, brain swelling and HT [123–125]. Ofthe different subtypes of MMP, MMP9 activity has been shown to increase incerebral ischemia even without administration of thrombolytics. In humans,this protein has been shown to be upregulated 10-fold in the infarct corecompared with contralateral tissues [126]. Moreover, administration of TPAcan cause specific upregulation of MMP9 only in ischemic endothelium butnot in uninjured tissues or micro vessels [127]. Also, MMP9 null mice wereshown to be partially protected from cerebral ischemia [128]. Broad spec-trum MMP inhibitors such as BB94, BB1191, FN439 etc., reduce TPA inducededema and HT in a variety of animal models. This further corroborates theevidence that MMPs have a key role in BBB vasculature and extracellularmatrix remodeling [129]. However, it appears that MMPs are also instru-mental in recovery from stroke and, as such, the beneficial effects of broadspectrum inhibitors may be outweighed by a longer recovery period [130].Indirect inhibitors of MMPs include antioxidants and free radicles scavengers[131]. Such agents reduce MMP9 activity and improve outcome [132]. Otherindirect inhibitors include anti-VEGF neutralizing antibodies, angiopoietin-1, activated protein c, statins, estrogen, as well as the antihypertensive can-desartan. Of special interest is the selective sulfonylurea inhibitor, glyburi-dem, which inhibits sur1-regulated NCca-atp channels and has been shownin animal models to reduce MMP-9 activity in the core and penumbra by halfwhen compared with saline controls. Unlike broad spectrum MMP inhibi-tors, glyburide does not directly inhibit MMP proteolysis and, furthermore,does not inhibit TPA induces clot lysis. Using a 4.5 h mechanical MCAomodel which was followed by administration of TPA, glyburide has beenshown to reduce brain swelling and improve the neurological score whenadministered at the time of recanalization [133]. Using a six hour mechanicalMCA occlusion model, which is notorious for increased incidence of symp-tomatic HT, administration of glyburide at time of recanalization signifi-cantly reduced brain swelling and symptomatic HT, while improvingneurological scores. Such data has repercussion on extending the therapeuticwindow beyond 4.5 h.

The effect of glyburidem as a regulator of MMP9 activity was also assessedin retrospective trials on diabetic patients who are already on this agent aspart of the medication regimen. Looking at patients with type 2 diabetes whopresent with non-lacunar acute stroke, prior and continued administration ofsulfonylurea drugs were linked to better neurological and functional out-comes when compare to diabetic patients who were not administered sul-fonylurea [134]. Furthermore, in a retrospective analysis of 220 patients withdiabetes mellitus who presented with acute stroke, after comparing patientswho were managed with sulfonylurea to those who were not, it was reportedthat none of the patients managed with sulfonyurea experienced sHT instriking difference to the control group which was not managed with sulfo-


nylurea. (Ann Neurology, manuscript in print, "Hemorrhagic transformationof ischemic stroke in diabetics on sulfonylureas"). It is therefore apparentthat inhibition of Sur1 via glyburide has a role at ameliorating TPA associ-ated HT which was shown to be mediated via MMP9. Yet, the acute effect ofglyburide in the non-diabetic population is yet to be analyzed. Currently,Glyburide Advantage in Malignant Edema and Stoke (GAMES) is an ongoingmulticenter phase II trial which aims to investigate the effect of IV glyburideon patients with severe anterior circulation ischemic stroke who are at highrisk for malignant cerebral edema (that is, baseline DWI lesion volumegreater than 82 ml) and likely also hemorrhagic transformation [135••].Indeed, it would be exciting to analyze the outcome as such findings maypave the road towards a glyburide/ rTPA combination therapy approach inthe future.

Hemorrhagic transformation- risk managementSeveral clinical risk scores have been proposed in an effort to predict the riskof ICH post thrombolysis. The hemorrhage after thrombolysis (HAT) scorewas designed after a literature review and was tested on two cohorts, theNINDS database as well as the authors’ primary center, yielding a pool of 400patients [136]. The authors used the NINDS definition of SICH (i.e., anyneurological worsening) when looking at 302 patients from the NINDS co-hort, and the ECASS definition ( i.e., 904 point NIHSS deterioration) whenlooking at 98 patients from a cohort at their own institution. The score itselfincorporates a five point scale which is composed of a history of diabetes oradmission glucose 9200 (1 pt), baseline NIHSS (1 pt for 15–20, 2 pt for920), and early CT hypo density (G1/3 MCA 1 pt, greater than 1/3 is granted2 pt). The authors reported that 78 % of patients with HAT score 93 devel-oped ICH, but agree that their study was limited since it was retrospective innature thus preventing validation of the symptomatic definition which initself was defined via two separate ways. Of note, the prediction of sICH viathe HAT score was stronger using the ECASS definition, though significancewas reached with both definitions (c-statistic for predicting any ICH was0.77 (0.66–0.88; pG0.001), and 0.88 (0.77–0.99; pG0.001) for SICH).Although the authors’ had a limited analysis of the HAT score onthrombolysis patients administered iv tpa, the score was recently vali-dated also using sonothrombolysis trials looking at patients with proxi-mal occlusions [137].

Analysis of the multicenter stroke survey (MCSS) database, using 1205patients of which only 481 had complete data for relevant variables, pro-posed the MCSS score [138]. This score uses a four point scoring system inwhich one point is given for age960, baseline NIHSS 910, glucose 9150 andplatelets count G150000. The sICH was defined in accord with the NINDSdefinition that is any amount of blood on CT, related to any clinical dete-rioration as reported by the treating physician (of which one point deterio-ration on an NIHSS was sufficient). The authors reported that a score903predicted 17.9 % of symptomatic ICH and 20 % of asymptomatic ICH with a95 % confidence interval.

In a recent study [139] Cucchiaria et al., attempted to validate the predic-tive value of both of the above risk scores using data from post TPA patients


in the SAINT I and II trials. In designing his study, the author defined sICH,similarly to the ECASS II definition, that is, as worsening in the NIHSS90 4points within 36 h in addition to evidence of any hemorrhage on a follow upimaging. The author modified the HAT score by using the Alberta strokeprogram early CT scan (ASPECTS) score to quantify initial CT hypo densitiesrather than the 1/3 MCA rule. It was assumed that an aspect score of 0–7correlated roughly to a hypo density on CT that is greater than 1/3 MCA.After applying the HAT and MCSS scores to the SAINT cohort database, theauthor reported that although both scores had some predictive value, neitherhad a significant discriminatory ability. The author proposed that in the fu-ture, supplementing these scores with currently investigated biomarkers suchas MMP9 etc., would potentially result in a more specific predictive scoringmethod.

Looking at data from the Get With The Guidelines Stroke (GWTG-stroke),Menon et al. [140] screened patients treated with IV TPA within three hoursof symptom onset, to derive and validate a prediction tool for sICH. Theauthor identified several independent predictors of sICH including increasedage, higher baseline NIHSS, higher systolic blood pressure and higher bloodglucose as well as Asian race and male sex, and incorporated all factors intoan aggregative GRASP score. The author used the NINDS definition of sICH,since the GWTG database did not have information on post hemorrhageNIHSS. The final score model was internally validated on a subset of theGWTG database and externally validated on the NINDS database (C statisticof 0.70 and 0.68, respectively) but thus far was not evaluated elsewhere.

Using the Safe implementation of treatments in stroke (SITS) internation-al stroke thrombolysis register Mayaza et al. [141] proposed a predicting riskscore for sICH defined by the SITS-MOST definition, that is a type 2 paren-chymal hemorrhage accompanied by deterioration of NIHSS90 4 points.The authors identified nine independent risk factors and implemented theseinto a scoring model, which was validated on the remaining half of the SITS-ISTR database population. These identified risk factors for sICH, includedbaseline NIHSS, serum glucose, systolic blood pressure, age, body weight,stroke onset to treatment time, aspirin or combined aspirin and clopidrogel,and finally a history of hypertension. The summative score ranged from 0 to12 and showed a 70 % increase in the rate of sICH for a score value90 to 10(as compared to a score of zero). Unlike the HAT and MCSS score, the SITSscore allows for a more rapid assessment since it did not require volumetricmeasurement of the initial infarct size (as does the HAT score) nor did itrequire delaying calculation of the predictive score until a blood plateletcount is measured ( as needed by the stroke survey group). Furthermore, theSITS score uses a more objective definition, when compared to the NINDSdefinition which is prone to variability by the investigator’s judgment, andwhich may be confounded by infarct edema, rather than hemorrhage, as anadditional factor contributing to clinical deterioration. However, unlike theECASS II definition which also uses a four point increase in NIHSS, the SITS-MOST definition for sICH is limited to parenchymal hemorrhages. It istherefore not surprising, using such overt definition for hemorrhage, that theauthors could report a score90 to ten to be associated with a six fold in-creased in sICH per ECASS II definition and a fourfold increase per NINDSdefinition for sICH.


The Canadian Stroke Network Registry was also utilized to predictclinical response after TPA. The I-Score scoring system is a compositeof age, sex, stroke severity, stroke subtype, admission glucose level, ad-mission disability and other risk factors including atrial fibrillation, CHF,and other comorbid conditions. In a gross analysis of the Canadianregistry, 12.4 % of the patients who received TPA has a subsequenthemorrhagic transformation, and in 6.9 % it was characterized assymptomatic hemorrhage. After subdivision of the i-score into threecategories, it was found that of the TPA administered patients those thatwere in the high risk category had a higher incidence of intracerebralhemorrhage of any type compared with the medium and low scoregroup. Indeed, hemorrhagic complications after TPA was three timeshigher in the high risk category when compared to the low risk category.A similar trend was observed with other neurological complications in-cluding 30 day mortality and disability. Despite the fact that the authorsreport an ethnic bias in the pool of patients at the Canadian registry,results have yet to be validated also in a large sized external samplecohort [142].

Hemorrhagic transformation- acute management– Evaluate airway and breathing capability and look for signs of

increased ICP– If any signs of airway compromise/ventilator failure/ aspiration or

increased ICP, intubate immediately& Ventilator settings should aim at normocarbia while minimizing

positive end expiratory pressure (PEEP), since increased PEEPresults in impaired cerebral perfusion secondary to decreased ve-nous return. Increased PEEP also results in reduced cerebral venousdrainage and exacerbated elevations in intracranial pressure.

– Consider measures of ICP control:& Elevate HOB to 30 degrees& In the hyperacute stage, hyperventilation may be induced

o Decreased CO2 promotes vasoconstrictiono Hyperventilate towards a PCO2 target of 30–35 mmHgo Effect is almost immediate, but incurs the risk of rebound

vasodilation and decreased perfusion& Long term goal is to maintain ICPG20 mmHg while keeping ce-

rebral perfusion pressure 970 mmHg

o If CPPG70, control BP with vasopressors such as dopa-mine or phenylephrine

o If CPP970, control BP with antihypertensives& Agitated patients should be started on a propofol or fentanyl drip& Consider mannitol

o Dose 0.25-0.6 g/Kg every 4 hourso Preferred in patients with CHF


o Obtain serial electrolyte measurements& Consider hyperosmolar saline

o Preferred in patients with renal failureo Obtain serial electrolytes

& If ICP is still refractory, consider barbiturate coma– Consult Neurosurgery

& Ventricular drains should be used for patients at risk for hydro-cephalus .

& ICP monitoring

o Consider if GCS of 8 or below and/ or clinical evidence oftranstentorial herniation, hydrocephalus or significant IVH

& Infratentorial /cerebellar hemorrhage greater than 3 cm is generallyapproached surgically due to concern for brain stem compression

& Opinions are not uniform regarding surgical treatment forsupratentorial hemorrhage

– Re-image & Re-evaluate& Determine subtype of hemorrhagic transformation as per ECASS

II criteria

o Note the HI subtype is generally regarded as a natural processand is not a sign of major concern

& If possible, obtain Perfusion and DWI sequences& If obtaining CTA, look for contrast extravasation into the hema-

toma as it’s predictive of hematoma expansion (spot sign). Earlyhematoma growth is worrisome.

& If a fluid level is seen within the hematoma, suspect an under-lying coagulopathy

& Continuous re-bleeding into damaged tissue is associated withpoor outcome

& Note, the half life of rTPA is limited to 45 min at the site of thethrombus

– Monitor& Transfer to an advanced level of care, preferably NICU setting& Advanced monitoring with brain tissue oxygen or cerebral micro di-

alysis may assist in identifying patients at high risk for deterioration.& Sonographic evaluation allows bedside close monitoring of HT. In

case of need, utilize echocontrast agents for better visualization [143]– Blood Pressure

& In the acute HT patient, close attention must be paid to reductionin BP variability. This could be achieved bya. when addressing hypertension, use an infusion rather than

scheduled doses, in an attempt to minutely control bloodpressure variations

b. when addressing hypotension, monitor intravascular fluidstatus and adopt an approach that includes albumin and


blood transfusions (as needed), in addition to traditionalpressors & crystalloids to achieve a more sustained responsewhich aims to target variability. Furthermore, avoidance of spo-radic fluid boluses is instrumental for minimizing BP variations

Blood pressure management in the setting of hemorrhagic transformationshould not differ from the current guidelines for management of spontane-ous ICH [144] i.e.:

& Patients with SBP 9200 mm HG or MAP9150 should be started onaggressive continuous IV antihypertensive infusion with BP moni-toring every 5 min.

& Patientswith systolic BP greater than 180mmHGorMAP9130mmHG

o If there is evidence of elevated ICP, consider ICP monitoringand reduction of BP towards a cerebral perfusion goal pres-sure of 60-80 mm HG

o If there is no evidence of elevated ICP, consider modest reduc-tion to a target MAP of 110 mmHG or target BP of 160/90 mmHg using either intermittent or continuous iv medications.

& Anticipating results from the ATACH II and INTERACT II ongoingclinical trials

– Ferritin management& In the acute HT patient, a lower ferritin level is desirable

& Studies endorse a goal of less than 145 ng/ml, consider loweringserum ferritin if needed

– Temperature management& In acute HT, optimal temperature goal should beGor0to 37 deg C

& Temperature should be lowered with acetaminophen and or coolingblankets

& Second line measures include

o advanced surface cooling techniqueso peripheral administration of chilled saline (4 deg C).o Refractory fever may require advanced cooling devices such as

adhesive surface cooling systems and endovascular heat ex-change catheters [145]

& Central Fever

o May result from of extravasation of blood to subarachnoid orintraventricular space

& Is a diagnosis of exclusion, to be made only after infection/throm-bosis/adverse drug effects have been ruled out& Shivering

o a natural outcome of lowering a body’s temperatureo does not serve neurological benefits since it increases cerebral

metabolic requirements anddiminished brain tissue oxygenation.o Buspirone, IV Magnesium infusion and surface counter

warming can be employed to suppress shivering.


– Glucose Management& Current guidelines recommend treatment with insulin titration in

patients with stroke and serum glucose 910 mmol/L (180 mg/dL) using an insulin sliding scale, yet the acute HT patient maybenefit from more aggressive measures to control sugar levelssuch as

o Insulin infusiono Glyburide administration

& Anticipating results from the SHINE and GAMES ongoing clinicaltrial

– Hemostatic Therapy& Obtain Type andCross and discontinue antiplatelets and anticoagulants

& Measure levels of Hg, HCT, PT, PTT platelet count and fibrinogen

& The optimal HG in acute sICH is unknown, however, if the ICH isnot of great extent common guidelines of transfusing when valuesare less than 7 or 8 should be employed

& If INR is elevated, reverse immediately

o FFP, Cryoprecipitate or clotting factor concentrate.Consider using these in the acuteHTpatient even if INR is normal

o Prothrombin complex concentrate is a reasonable alternative to FFPand may have fewer complications

o Vitamin K for long term and sustained reversal& If PTT is elevated secondary to heparin

Reverse with protamine sulfate 1 mg for every 100 IU of heparin ad-ministered

& The use of platelets transfusion for patients on antiplatelets is unclearand considered investigational

& As per result from the FAST trial, no difference in disability or mor-tality at 90d was noted with activated recombinant factor VII.

– Anticonvulsant Therapy& cortical blood may serve as a trigger for seizures& continuous EEG may be of greater benefit in detecting subclinical

electrographic seizures& currently, class II level B recommendations specify that it

should be utilized in patients with depressed level of con-sciousness out of proportion to level of brain injury

& for acute seizures administer& IV lorazepam 0.05-1/0 mg/kg& followed by IV load of fosphenytoin (15-20 mg/kg), valproic

acid (15–45 mg/kg), or phenobarbital (15-20 mg/kg)& Prophylactic anticonvulsant therapy should not be routinely used

( class III level B rec)– Prophylaxis

& Immobilized state predisposes to deep vein thrombosis andpulmonary embolism


o Pneumatic compression devices should be placed on admissiono Low dose heparin on hospital day 2, in patients with ICH,

was shown to decrease the incidence of PE without increase inincidences of re-bleeding

& Stress ulcers are common inpatientswithhemorrhagic transformation

o all patients should be on prophylactic proton pump inhibi-tors or H2 blockers

– Fluids/ Electrolytes& Electrolyte derangements are common in critical illness necessitation& Such electrolyte derangements may contribute to delirium, seizures

and cardiac complications.& Isotonic fluids should be used for maintenance and a eunatremia

goal should be monitored with frequent sodium levels.

DisclosureDr. Sheth has received grant support from Remedy Pharmaceuticals.Dr. Weiser reported no potential conflicts of interest relevant to this article.

References and Recommended ReadingPapers of particular interest, published recently, have beenhighlighted as:•• Of major importance

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Clinical Predictors and Management of Hemorrhagic Transformation