Cerebral Haemodynamics following Acute Ischaemic Stroke: Effects of Stroke Severity and Stroke Subtype

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1 Received: November 27, 2017 Accepted fter revision: Februry 7, 2018 Published online: July 11, The Author(s) Published by S. Krger AG, Bsel This rticle is licensed under the Cretive Commons Attribution-NonCommercil-NoDerivtives 4.0 Interntionl License (CC BY-NC-ND) ( Usge nd distribution for commercil purposes s well s ny distribution of modified mteril requires written permission. Originl Pper Cerebrl Hemodynmics following Acute Ischemic Stroke: Effects of Stroke Severity nd Stroke Subtype Osin Llwyd Angel S.M. Slinet, b Ronney B. Pneri Mn Y. Lm Nzi P. Seed Fion Brodie Edson Bor-Seng-Shu b Thompson G. Robinson Ricrdo C. Nogueir b Deprtment of Crdiovsculr Sciences Cerebrl Hemodynmics in Ageing nd Stroke Medicine Reserch Group, University of Leicester, Leicester, UK; b Neurology Deprtment, Hospitl ds Clinics, School of Medicine, University of São Pulo, São Pulo, Brzil Keywords Blood flow velocity Cerebrl utoregultion Acute stroke Stroke subtype Stroke severity Abstrct Bckground: Acute ischemic stroke (AIS) ptients often show impired cerebrl utoregultion (CA). We tested the hypothesis tht CA impirment nd other ltertions in cerebrl hemodynmics re ssocited with stroke subtype nd severity. Methods: AIS ptients (n = 143) were mlgmted from similr studies. Dt from bseline (< 48 h stroke onset) physiologicl recordings (bet-to-bet blood pressure [BP], cerebrl blood flow velocity (CBFV) from bilterl insontion of the middle cerebrl rteries) were clculted for men vlues nd utoregultion index (ARI). Differences were ssessed between stroke subtype (Oxfordshire Community Stroke Project [OCSP] clssifiction) nd severity (Ntionl Institutes of Helth Stroke Scle [NIHSS] score < 5 nd 5 25). Correltion coefficients ssessed ssocitions between NIHSS nd physiologicl mesurements. Results: Thirty-two percent of AIS ptients hd impired CA (ARI < 4) in ffected hemisphere (AH) tht ws similr between stroke subtypes nd severity. CBFV in AH ws comprble between stroke subtype nd severity. In unffected hemisphere (UH), differences existed in men CBFV between lcunr nd totl nterior circultion OCSP subtypes (42 vs. cm s 1, p < 0.01), nd mild nd moderte-to-severe stroke severity (45 vs. 51 cm s 1, p = 0.04). NIHSS ws ssocited with peripherl (distolic nd men Osin Llwyd nd Angel S.M. Slinet re joint first uthors. Ricrdo C. Nogueir Neurology Deprtment, Hospitl ds Clinics School of Medicine, University of São Pulo Avenid Doutor Arnldo, 455, Cerqueir Césr, São Pulo, SP (Brzil) E-Mil gmil.com

2 81 rteril BP) nd cerebrl hemodynmic prmeters (CBFV nd ARI) in the UH. Conclusions: AIS ptients with different OCSP subtypes nd severity hve homogeneity in CA cpbility. Cerebrl hemodynmic mesurements in the UH were distinguishble between stroke subtype nd severity, including the ssocition between deteriorting ARI in UH with stroke severity. More studies re needed to determine their clinicl significnce nd to understnd the determinnts of CA impirment in AIS ptients The Author(s) Published by S. Krger AG, Bsel Introduction Trnscrnil Doppler ultrsound hs been widely used to evlute cerebrl hemodynmics in cute ischemic stroke (AIS) ptients, s it offers non-invsive nd rel-time monitoring of cerebrl blood flow velocity (CBFV). In prticulr, the ssessment of cerebrl utoregultion (CA), which reflects chnges in CBF in reltion to chnges in blood pressure (BP), hs provided further understnding of cerebrl hemodynmic control [1]. Whilst previous studies hve reported impirment of CA following cute stroke [2, 3], there re limited dt on the effects of stroke subtype nd severity. Corticl stroke ppers to be ssocited with reduced CA, more often in the ffected hemisphere (AH), wheres subcorticl stroke my be ssocited with bilterl impirment [4, 5]. Stroke severity my lso be relevnt, with moderte-to-severe stroke exhibiting greter CA impirment compred to minor stroke [6 9]. However, smll smple size, nd methodologicl heterogeneity in both dt collection nd nlysis limit informed comprison between studies [10]. The Cerebrl Hemodynmics in Ageing nd Stroke Medicine (CHiASM) t the University of Leicester hs longstnding interest in studies of cerebrl hemodynmic control mechnisms in the cute nd recovery phses of AIS [7, 11 14]. Together with collbortors from the Hospitl ds Clinics (São Pulo, Brzil), trined in cerebrl hemodynmic ssessment in Leicester, we hve developed lrge two-centre prospective dtbse of AIS ptients, utilising similr techniques in dt cquisition nd nlysis tht llow the interprettion of the effects of stroke severity nd subtype on cerebrl hemodynmic responses. We tested the hypothesis tht stroke subtype or stroke severity significntly ffects CA nd consequently CBF precipitted by fluctutions in BP. Methods All investigtors were trined t the sme lbortory (University of Leicester, UK), nd cquired physiologicl dt to stndrd dt collection nd nlysis protocol. AIS ptients dmitted to the University Hospitls of Leicester NHS Trust (Leicester, UK), since 2007, or to the Hospitl ds Clinics (São Pulo, Brzil), since 2015, nd eligible for inclusion into ongoing studies of cerebrl hemodynmics in AIS, were recruited nd provided informed consent in complince with locl ethics committee pprovls. All studies hd common inclusion criteri: ptients with clinicl dignosis of AIS, ged 18 yers, ble to prticipte in study mesurements, nd informed consent; common exclusion criterion ws co-morbidity with life expectncy less thn 3 months. In ddition, ptients were excluded from the dtbse if: () missing key informtion (ge, sex, nd clssifiction of stroke subtype ccording to Oxfordshire Community Stroke Project [OCSP] clssifiction), (b) poor dt qulity, (c) duplictes rising from overlpping studies, (d) AIS clssified s posterior circultion stroke, (e) physiologicl mesurements performed fter 48 h from stroke onset.

3 82 The sme protocol ws used for ll studies. Briefly, bet-to-bet BP ws recorded continuously using the Finpres or Finometer devices (FMS, Finpres Mesurement Systems, Arnhem, Netherlnds). Hert rte (HR) ws recorded using 3-led electrocrdiogrm, nd end-tidl CO 2 (etco 2 ) ws mesured vi nsl prongs (Slter Lbs) by n infrred cpnogrph (Cpnocheck Plus nd Trnsmi MX-200 in Leicester nd São Pulo, respectively). Bilterl insontion of the middle cerebrl rteries ws performed using trnscrnil Doppler (Visys Compnion III; Visys Helthcre nd Doppler box, DWL for Leicester nd São Pulo, respectively) with 2-MHz probe, secured in plce using hed-frme. Subjects were in supine position. Systolic nd distolic BP ws mesured by brchil sphygmomnometry followed by 15-min stbilistion nd 5-min bseline recording. When more thn one bseline recording ws vilble, the first cceptble recording ws used for further nlysis. Stroke subtype ws defined by the OCSP clssifiction; stroke severity ws ssessed by the NIHSS on hospitl dmission nd t the time of cerebrl hemodynmic ssessment, with further ctegoristion by mild (NIHSS 5) [15] nd moderte-to-severe stroke (NIHSS 6 25) [16]. Dt Anlysis This hs been described in detil previously [17]. In brief, dt were simultneously recorded onto dt cquisition system (PHYSIDAS, Deprtment of Medicl Physics, University Hospitls of Leicester) for subsequent off-line nlysis. BP ws clibrted t the strt of ech recording using systolic nd distolic vlues from brchil sphygmomnometry. The R R intervl ws utomticlly mrked from the electrocrdiogrm nd men BP nd CBFV vlues were clculted for ech crdic cycle. If the etco 2 recording ws not consistent due to periods of brething through the mouth, the highest etco 2 vlue ws used. Autoregultion index (ARI), which represents dynmic CA, ws extrcted by using the best lest-squres fit between the CBFV step response nd one of the 10 model ARI curves proposed by Tiecks et l. [18]. Vlues of ARI were only ccepted for further nlyses if strict conditions were met regrding the significnce of the coherence between men rteril BP CBFV nd the normlised men squre error of fit to Tiecks model [19]. Sttisticl Anlysis Men vlues of ech vrible were clculted from the entire bseline recording. Tests for normlity were performed using the Shpiro-Wilk normlity test. Dt re presented s medin nd interqurtile rnge (25th 75th percentile) nd men (SD) unless stted otherwise. Prmeter vlues were considered outliers nd excluded from further nlysis if they were ±3 SD from the men for ll stroke ptients. Differences between vlues derived from the AH or unffected hemisphere (UH) were ssessed with pired Student s t test or the Wilcoxon test. Differences in vribles between OCSP subtypes were ssessed using χ 2 test, Fisher s exct test, ANOVA or Kruskl-Wllis test, followed by Tukey s or Dunn s multiple comprison test. Differences in vribles between ctegorised NIHSS were ssessed with Fisher s exct test, unpired Student s t test or Mnn-Whitney test. Associtions between vribles were tested using liner regression correltion coefficient or Spermn s rnk test s pproprite, where NIHSS ws considered s continuous vrible. A p vlue of < 0.05 ws defined s sttisticl significnce. Results Study Popultion Dt for 143 AIS ptients (105 Leicester; 38 São Pulo) of men ge 65 yers (SD 13; 37% femle) with good qulity bseline recordings were included. Key bseline chrcteristics re

4 83 Tble 1. Key bseline ptient chrcteristics Vrible n Totl ptients 143 Demogrphics Femle Age, yers 143 Ptient history Smoker Ex-smoker Ischemic hert disese Cerebrovsculr disese Dibetes mellitus Hypertension Antihypertensive therpy Sttin therpy Aspirin/ntipltelet/wrfrin Ipsilterl ICA stenosis >50% Contrlterl ICA stenosis >50% AIS fetures LACS PACS TACS Onset to recording, h Time of recording, h Thrombolysed Ipsilterl side, R/L Admission NIHSS Assessment NIHSS / (37) 65 [13] (19) (33) (25) (18) (14) (50) () (29) (23) () (5) (37) (46) (17) 19 (5 30) 13:00 (11:11 15:30) (49) (49/51) 7 (4 12) 5 (3 10) Dt re presented s n (% of vilble dt), men [stndrd devition] or medin (interqurtile rnge, 25 75th percentile), s pproprite. n, number of prticipnts; ICA, internl crotid rtery; AIS, cute ischemic stroke; R, right; L, left; NIHSS, Ntionl Institutes of Helth Stroke Scle; LACS, lcunr stroke syndrome; PACS, prtil nterior circultion stroke syndrome; TACS, totl nterior circultion stroke syndrome. described in Tble 1. Of these, 115 ptients hd bilterl middle cerebrl rtery recordings; 9 hd unilterl recordings only of the AH nd 19 only of the UH. Assessments of cerebrl hemodynmic prmeters were undertken medin of 19 h (IQR 5 30) fter stroke onset, with 49% of ptients treted with intrvenous thrombolysis. Influence of Stroke Subtype Ptient chrcteristics nd peripherl nd cerebrl hemodynmic dt re described in Tble 2 by ech stroke subtype; lcunr (LACS, n = ), prtil (PACS, n = ) nd totl nterior circultion infrcts (TACS, n = ). TACS ptients were more likely to hve higher NIHSS nd lower distolic BP vlues t the time of hemodynmic ssessment. With respect to differences in cerebrl hemodynmic prmeters between AH nd UH, systolic, men nd distolic CBFV were significntly higher in the UH in the TACS ptients only. Regrding the comprison between stroke subtypes for AH nd UH, only the UH hd significnt differences for systolic, men nd distolic CBFV in the LACS compred to TACS ptients, nd dditionlly compred to PACS ptients for distolic CBFV lone. A poor goodness of fit to Tieck s model of CA ws

5 84 Tble 2. Ptient chrcteristics nd peripherl nd cerebrl hemodynmic prmeters by stroke subtype Vrible LACS PACS TACS p vlue n n n Demogrphics Femle 20 (38) 22 (33) 11 Age, yers 67 [12] 65 [14] AIS Fetures Assessment NIHSS NIHSS <5 NIHSS 6 25 NIHSS >25 Thrombolysed Onset to recording, h Peripherl hemodynmic prmeters MABP, mm Hg Systolic BP, mm Hg Distolic BP, mm Hg HR, bets/min etco 2, mm Hg Cerebrl hemodynmic prmeters Men CBFV, cm s 1 A Men CBFV, cm s 1 U Systolic CBFV, cm s 1 A Systolic CBFV, cm s 1 U Distolic CBFV, cm s 1 A Distolic CBFV, cm s 1 U ARI, rbitrry units A ARI, rbitrry units U ARI <4 A ARI <4 U (1 4) ǂ, # (79) (21) (23) 22 (14 36) 102 [16] 149 [23] 81 [14] # 71 [10] 36 [3] 40 [12] 42 [13] # 64 [16] 67 [18] # 25 [10] 26 [10] ǂ, # 4.6 ( ) 4.4 ( ) (33) (27) (3 9) # (51) (49) (62) 15 (3 30) 99 [13] 144 [23] 77 [12]) 71 [13] 36 [3] 43 [16] 48 [16] [] 75 [22] 28 [11] 31 [12] 4.6 ( ) 4.8 ( ) (33) (23) (46) 60 [15] 15 (10 18) (13) (83) (4) (52) 16 (6 28) 94 [11] 142 [16] 72 [12] 75 [14] 36 [3] 44 [15]* [19] 67 []* 86 [25] 29 [11]* 36 [13] 4.2 ( ) 4.1 ( ) (28) (47) <0.001 <0.001 < < < < Dt re presented s n (% of vilble dt), men [stndrd devition] or medin (interqurtile rnge, 25th 75th percentile), s pproprite. p vlue, ANOVA or Kruskl-Wllis test between OCSP subtypes, followed by Tukey s or Dunn s multiple comprison test. n, number of prticipnts; AIS, cute ischemic stroke; NIHSS, Ntionl Institutes of Helth Stroke Scle; MABP, men rteril blood pressure; HR, hert rte; etco 2, end tidl CO 2 ; CBFV, cerebrl blood flow velocity; ARI, utoregultion index; A, ffected hemisphere; U, unffected hemisphere; LACS, lcunr stroke syndrome; PACS, prtil nterior circultion stroke syndrome; TACS, totl nterior circultion stroke syndrome. * p < 0.05 vs. unffected side. ǂ p < 0.05 vs. PACS. # p < 0.05 vs. TACS. Outlier removed from dtset. found in 9 recordings from the AH nd 13 from the UH. These vlues were not included in further ARI nlysis, giving totl of 115 nd 121 sets of dt, respectively, 99 of these bilterl. No differences in ARI between the AH nd UH or between the stroke subtypes were observed, including the number tht hd ARI < 4 tht could be suggestive of impired CA (Tble 2) [20]. Influence of Stroke Severity AIS ptients were ctegorised into mild (n = 65) nd moderte-to-severe (n = ) stroke severity. Ptient groups were of similr ge nd sex, with significntly greter proportion of TACS nd ptients thrombolysed in the moderte-to-severe stroke group (Tble 3). At the time of hemodynmic ssessment, mild compred to moderte-to-severe stroke ptients were more likely to hve lower HR, nd men nd distolic CBFV in the UH; with hemodynmic ssessment occurring lter from stroke onset. With respect to differences in cerebrl hemodynmic prmeters between AH nd UH, systolic nd distolic CBFV in the UH ws higher in the moderte-to-severe stroke popultion. There were no differences observed in

6 85 Tble 3. Ptient chrcteristics nd peripherl nd cerebrl hemodynmic prmeters by mild nd moderte-to-severe stroke severity Vrible Mild stroke (NIHSS 5) Moderte-to-severe stroke (NIHSS 6 25) p vlue n n Demogrphics 65 Femle 26 (40) Age, yers 65 [12] AIS fetures LACS PACS TACS Thrombolysed Onset to recording, h Peripherl hemodynmic prmeters MABP, mm Hg Systolic BP, mm Hg Distolic BP, mm Hg HR, bets/min etco 2, mm Hg Cerebrl hemodynmic prmeters Men CBFV, cm s 1 A Men CBFV, cm s 1 U Systolic CBFV, cm s 1 A Systolic CBFV, cm s 1 U Distolic CBFV, cm s 1 A Distolic CBFV, cm s 1 U ARI, rbitrry units A ARI, rbitrry units U ARI <4 A ARI <4 U (51) ǂ (45) (5) ǂ (33) ǂ 21 (11 31) ǂ 100 [16] 145 [23] 79 [13] 69 [12] ǂ 35 [3] 41 [13] 45 [14] ǂ 64 [19] 71 [19] 26 [10] 28 [10] ǂ 5.0 ( ) 5.1 ( ) (28) (22) (43) 64 [14] (16) (50) (34) (60) 10 (3 27) 98 [13] 143 [22] 76 [13] 74 [11] 36 [3] 43 [17] 51 [18] 67 [25]* 79 [25] 28 [12]* 33 [13] 4.3 ( ) 4.4 ( ) (33) (28) < < Dt re presented s n (% of vilble dt), men [stndrd devition] or medin (interqurtile rnge, 25th 75th percentile), s pproprite. p vlue, Fisher s exct test, unpired t test or Mnn-Whitney test between mild nd moderte-tosevere stroke. n, number of prticipnts; AIS, cute ischemic stroke; NIHSS, Ntionl Institutes of Helth Stroke Scle; MABP, men rteril blood pressure; HR, hert rte; etco 2, end tidl CO 2 ; CBFV, cerebrl blood flow velocity; ARI, utoregultion index; A, ffected hemisphere; U, unffected hemisphere; LACS, lcunr stroke syndrome; PACS, prtil nterior circultion stroke syndrome; TACS, totl nterior circultion stroke syndrome. * p < 0.05 vs. unffected side. ǂ p < 0.05 vs. greter NIHSS. Outlier removed from dtset. ARI between the AH nd UH or between mild nd moderte-to-severe stroke ptients, including those with ARI < 4 (Tble 3). Stroke severity hd significnt correltion with some peripherl (men nd distolic BP) nd cerebrl hemodynmic prmeters (Tble 4). For every 4-point NIHSS score increse, there ws n increse in the UH of 2.8, 2.1 nd 1.7 (cm s 1 ) in systolic, men nd distolic CBFV, respectively. In ddition, 4-point increse in NIHSS ws ssocited with 1.8 nd 2.2 mm Hg reduction in men nd distolic BP or 0.3 reduction in ARI in the UH. However, no significnt correltion with stroke severity ws observed for cerebrl hemodynmic prmeters in the AH (Tble 4).

7 86 Tble 4. Influence of stroke severity, ssessed by NIHSS, on peripherl nd cerebrl hemodynmic prmeters n CC Regression coefficient p vlue Peripherl prmeters MABP (mm Hg) Systolic BP (mm Hg) Distolic BP (mm Hg) HR (bets/min) etco 2 (mm Hg) Cerebrl hemodynmics Men CBFV (cm s 1 ) A Men CBFV (cm s 1 ) U Systolic CBFV (cm s 1 ) A Systolic CBFV (cm s 1 ) U Distolic CBFV (cm s 1 ) A Distolic CBFV (cm s 1 ) U ARI (rbitrry units) A ARI (rbitrry units) U NIHSS NIHSS NIHSS NIHSS NIHSS NIHSS NIHSS NIHSS NIHSS NIHSS NIHSS NIHSS NIHSS < < <0.01 p vlue, Person or Spermn s rnk test s pproprite. n, number of prticipnts; CC, correltion coefficient; MABP, men rteril blood pressure; HR, hert rte; etco 2, end tidl CO 2 ; CBFV, cerebrl blood flow velocity; ARI, utoregultion index; A, ffected hemisphere; U, unffected hemisphere; NIHSS, Ntionl Institutes of Helth Stroke Scle. Discussion This study demonstrted tht overll mny AIS ptients hd CA impirment, with n ARI below 4 during the first 48 h following stroke onset; 32% in the AH lone, 21% with bilterl impirment. There were no significnt differences in ARI between stroke subtypes, defined by OCSP, or stroke severity, defined by NIHSS, except for smll reduction in ARI in the UH with incresing stroke severity. With respect to other mesures of cerebrl hemodynmics, no differences were observed for the AH by stroke subtype or severity. In the UH, TACS subtype nd moderte-to-severe stroke severity ws ssocited with incresed CBFV. Influence of Stroke Subtype Few studies hve evluted the effect of stroke subtype on CA in the cute phse [2, 4, 5], reporting bilterl impirment of CA with lcunr infrction nd impired CA predominntly in the AH in lrge vessel stroke [4, 5]. Nonetheless, definitive conclusions re limited by smll smple sizes nd methodologicl differences, nd the present study llowed chnges to be ssessed in lrge cohort of AIS ptients using comprble methods. Our dt support differences in CBFV between corticl (TACS) nd subcorticl (LACS) stroke, interestingly in fvour of incresed CBFV in the UH in TACS. A number of possible explntions could be put forwrd for this. First, subcorticl stroke my be ssocited with smll vessel disese, cused by dibetes nd chronic hypertension [4, 5], nd is more likely to led to bilterl deteriortion in cerebrl hemodynmics [21]. Secondly, incresed CBFV my be response to the lrge vessel occlusion with recruitment of leptomeningel collterl circultion from the UH. However, CBFV mesured in the UH ws similr to tht reported in helthy individuls [17], nd high levels of thrombolysis t 49% in the popultion studied my be ssocited with recnliztion. Thirdly, CBFV in the UH my reflect cerebrl stel, with there being previous

8 87 reports in stroke ptients where perfusion to the UH is ugmented [22]. Finlly, ssocited ICA stenosis my hve resulted in previous chnges in cerebrl hemodynmics, prticulrly collterl blood flow, though only 20% of ptients hd significnt ICA stenosis greter thn 50%, nd ll of these ptients hd different CBFV. Nonetheless, despite CBFV chnges, there ws no significnt effect of stroke subtype on CA, s ssessed by the ARI. This is in contrst to some of the previous literture [2, 4, 5]. Aprt from the non-sttionrity of dynmic CA [23], other possibilities for the disprity include: previous studies on AIS ptients contining smller smple sizes, from selected popultions, different methodology to define stroke subtype [4], nd differences in prmeters dopted to quntify CA [10]. Influence of Stroke Severity Minor stroke [9], smller stroke volumes [3] nd/or successful thrombolytic therpy [8] hve been ssocited with no dverse impct on CA. Wheres lrge rtery stroke [2] with ssocited incresed severity [3], unsuccessful thrombolysis [9] or hemorrhgic trnsformtion [] my be ssocited with impired CA, prticulrly during the first few dys of dmission, nd hve n dverse impct on neurologicl outcome [25]. The present study demonstrted n overll non-significnt reduction in ARI in moderte-to-severe compred to mild stroke. This could be due to the hemodynmic ssessment occurring on verge 11 hours lter in the mild stroke ptients. However, the incresing NIHSS score ws wekly, but significntly, ssocited with deteriorting ARI in the UH only. Furthermore, differences in CBFV relted to stroke severity were lso only observed in the UH. Stroke severity my be ssocited with crdiovsculr complictions, including utonomic dysfunction [26]. Though there ws incresed sympthetic ctivtion (s evidenced by HR) in ptients with moderte-to-severe stroke severity, we found no correltion between HR nd NIHSS. In ddition, there my be more dependency on broreceptor sensitivity when CA is impired [27], which my be diminished when there is incresed sympthetic ctivity nd higher HR, s when ptients suffer stroke of greter severity [28, 29]. Finlly, incresed BP is well documented following stroke, though we found n inverse ssocition between BP nd NIHSS score, which is unsurprising in tht more likely hypertensive LACS ptients will hve lower NIHSS scores. Nonetheless, our dt should be interpreted with cution s there were fewer severe stroke ptients included, nd further studies of the effect of stroke severity on cerebrl hemodynmics re wrrnted. Study Limittions There re number of limittions to our study. First, though the OCSP is widely used clinicl clssifiction, it does not consider underlying stroke etiology, which my be more relevnt in the potentil impct on cerebrl hemodynmics [30]. Secondly, NIHSS ws not lwys tken on dmission nd t ssessment, so mximum stroke severity could not be considered in further nlysis. In ddition, NIHSS ws undertken by severl investigtors. Thirdly, ARI ws mesured from spontneous fluctutions between BP nd CBF, though it is still to be determined whether smll BP fluctutions re the best method for ssessing CA [31]. The ffected side hd fewer good qulity recordings nd poor goodness of fit to Tieck s model of CA, which could hve dded bis to some dt sets. Finlly, lthough, to our knowledge, this is currently the lrgest CA dtbse of AIS ptients to report cerebrl hemodynmic chnges, its size remins limited to definitely ssess the effects of stroke subtype nd severity.

9 88 Conclusion This lrge cohort demonstrted tht cerebrl hemodynmics represented by CBFV is significntly different ccording to stroke subtype nd severity in the UH with higher vlues following TACS. This is new finding tht should be explored in future studies s prognostic mrker in this sub-popultion, prticulrly the impct of successful recnliztion therpies. Our study corroborted previous findings tht demonstrted n impirment of CA during the first 48 h; with this lrge smple, we could demonstrte tht this impirment is not influenced by stroke subtype nd is poorly ssocited with stroke severity in the UH. Acknowledgments T.G.R. is Ntionl Institute for Helth Reserch Senior Investigtor. Disclosure Sttement The uthors declre tht they hve no conflicts of interest. Funding Sources This study ws supported by UK Engineering nd Physicl Sciences Reserch Council (grnt No. EP/K041207/1) nd São Pulo Reserch Foundtion (FAPESP N. 2014/ & 2013/259-0). References 1 Pneri RB: Cerebrl utoregultion: from models to clinicl pplictions. Crdiovsc Eng 2008; 8: Xiong L, Tin G, Lin W, Wng W, Wng L, Leung T, Mok V, Liu J, Chen X, Wong K: Is dynmic cerebrl utoregultion bilterlly impired fter unilterl cute ischemic stroke? J Stroke Cerebrovsc Dis 2017; 26: Cstro P, Serrdor JM, Roch I, Sorond F, Azevedo E: Efficcy of cerebrl utoregultion in erly ischemic stroke predicts smller infrcts nd better outcome. Front Neurol 2017; 8: Immink RV, Vn Montfrns G, Stm J, Kremker JM, Dimnt M, Vn Lieshout JJ: Dynmic cerebrl utoregultion in cute lcunr nd middle cerebrl rtery territory ischemic stroke. Stroke 2005; 36: Guo Z-N, Liu J, Xing Y, Yn S, Lv C, Jin H, Yng Y: Dynmic cerebrl utoregultion is heterogeneous in different subtypes of cute ischemic stroke. PLoS One 2014; 9:e Reinhrd M, Wihler C, Roth M, Hrloff A, Niesen WD, Timmer J, Weiller C, Hetzel A: Cerebrl utoregultion dynmics in cute ischemic stroke fter rtpa thrombolysis. Cerebrovsc Dis 2008; 26: Atkins ER, Brodie FG, Rfelt SE, Pneri RB, Robinson TG: Dynmic cerebrl utoregultion is compromised cutely following mild ischemic stroke but not trnsient ischemic ttck. Cerebrovsc Dis 2010; 29: Reinhrd M, Rutsch S, Lmbeck J, Wihler C, Czosnyk M, Weiller C, Hetzel A: Dynmic cerebrl utoregultion ssocites with infrct size nd outcome fter ischemic stroke. Act Neurol Scnd 2012; 125: Chen J, Liu J, Xu W-H, Xu R, Hou B, Cui L-Y, Go S: Impired dynmic cerebrl utoregultion nd cerebrovsculr rectivity in middle cerebrl rtery stenosis. PLoS One 2014; 9:e Meel-vn den Abeelen ASS, Simpson DM, Wng LJY, Slump CH, Zhng R, Trumi T, Rickrds CA, Pyne S, Mitsis GD, Kostoglou K, Mrmrelis V, Shin D, Tzeng YC, Ainslie PN, Gommer E, Müller M, Dordo AC, Smielewski P, Yelicich B, Puppo C, Liu X, Czosnyk M, Wng CH, Novk V, Pneri RB, Clssen JAHR: Between-centre vribility in trnsfer function nlysis, widely used method for liner quntifiction of the dynmic pressureflow reltion: The CARNet study. Med Eng Phys 2014; 36: Seed NP, Pneri RB, Horsfield M, Robinson TG: Does stroke subtype nd mesurement technique influence estimtion of cerebrl utoregultion in cute ischemic stroke? Cerebrovsc Dis 2013; 35:

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