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APPENDIXSupplementary Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart of our analysis.Supplementary Figure 2.1. Leave-one-out analysis for pairwise antegrade cerebral perfusion (ACP) versus deep hypothermic circulatory arrest (DHCA) comparison for post-operative stroke. Supplementary Figure 2.2. Leave-one-out analysis for pairwise antegrade cerebral perfusion (ACP) versus deep hypothermic circulatory arrest (DHCA) comparison for operative mortality.Supplementary Figure 2.3. Leave-one-out analysis for pairwise retrograde cerebral perfusion (RCP) versus deep hypothermic circulatory arrest (DHCA) comparison for post-operative stroke.Supplementary Figure 2.4. Leave-one-out analysis for pairwise retrograde cerebral perfusion (RCP) versus deep hypothermic circulatory arrest (DHCA) comparison for operative mortality.Supplementary Figure 2.5. Leave-one-out analysis for pairwise antegrade cerebral perfusion (ACP) versus retrograde cerebral perfusion (RCP) comparison for post-operative stroke.Supplementary Figure 2.6. Leave-one-out analysis for pairwise antegrade cerebral perfusion (ACP) versus retrograde cerebral perfusion (RCP) comparison for operative mortality.Supplementary Figure 3.1. Subgroup analysis comparing bilateral and unilateral antegrade cerebral perfusion (ACP) versus retrograde cerebral perfusion (RCP) for post-operative stroke (p for intergroup comparison = 0.89).Supplementary Figure 3.2. Subgroup analysis comparing bilateral and unilateral antegrade cerebral perfusion (ACP) versus deep hypothermic circulatory arrest (DHCA) for post-operative stroke (p for intergroup comparison = 0.24).Supplementary Figure 4.1. Subgroup analysis comparing antegrade cerebral perfusion (ACP) versus deep hypothermic circulatory arrest (DHCA) for post-operative stroke in the different quartiles of circulatory arrest time (p for intergroup comparison = 0.01).Supplementary Figure 4.2. Subgroup analysis comparing retrograde cerebral perfusion (RCP) versus deep hypothermic circulatory arrest (DHCA) for post-operative stroke in the different quartiles of circulatory arrest time (p for intergroup comparison = 0.003).Supplementary Figure 4.3. Subgroup analysis comparing antegrade cerebral perfusion (ACP) versus retrograde cerebral perfusion (RCP) for post-operative stroke in the different quartiles of circulatory arrest time (p for intergroup comparison = 0.09).Supplementary Figure 5. Rank order for different treatment groups using rank scores with probability rank (P-scores), with the greatest reduction in outcomes in different treatment groups (antegrade cerebral perfusion [ACP], retrograde cerebral perfusion [RCP], and deep hypothermic circulatory arrest [DHCA]) where P-scores closer to 1 equate to the probability the therapy leads to the greatest reduction. Supplementary Table 1. Ovid MEDLINE search strategy.Ovid MEDLINE(R) ALL 1946 to August 10, 2018; Searched on Aug 13, 2018 (No date, language, or article type restrictions)Line # | Search string 1(antegrade adj3 (cerebral perfusion or brain perfusion or cerebral circulation or cerebrovascular circulation or cerebral blood flow or cerebrovascular blood flow or brain circulation or brain blood flow)).mp.2(regional low-flow cerebral perfusion or regional low-flow brain perfusion or selective cerebral perfusion or selective brain perfusion or low-flow cerebral perfusion or low-flow brain perfusion or continuous cerebral perfusion or continuous brain perfusion or regional cerebral perfusion or regional brain perfusion).mp.31 or 24(retrograde adj3 (cerebral perfusion or brain perfusion or cerebral circulation or cerebrovascular circulation or cerebral blood flow or cerebrovascular blood flow or brain circulation or brain blood flow)).mp.5Circulatory Arrest, Deep Hypothermia Induced/6(hypothermic circulatory arrest or hypothermic cardiac arrest or hypothermic circulation arrest or hypothermia induced circulatory arrest or hypothermia induced cardiac arrest or hypothermia induced circulation arrest or hypothermic arrest or DHCA).mp.75 or 683 and 493 and 7104 and 7118 or 9 or 10Supplementary Table 2. Demographics of included patients.Age (Mean±SD)Female (%)Hypertension (%)Peripheral Vascular Disease (%)Chronic lung disease (%)Diabetes (%)Smoking (%)Previous CVA/ stroke/ TIA/neurologic issue (%)Coronary artery disease (%)Study/YearACPRCPDHCAACPRCPDHCAACPRCPDHCAACPRCPDHCAACPRCPDHCAACPRCPDHCAACPRCPDHCAACPRCPDHCAACPRCPDHCAAhn/1997 154.349.749.758.371.457.1NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRAkashi/2000 266.1 +/- 10.764.4 +/- 18.8NR42.741.8NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNR1820NRNRNRNRAlamanni/1995 362.1 +/- 7NR58.7 +/- 1225NR26.4NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRApaydin/2009 460 (13)54 (12)56 (12)NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRApostolakis/2008 56160NR30.420NR91.372NRNRNRNR47.856NR56NRNRNRNR0.090.04NRNRNRNRArnaoutakis/2017 661.9 (13.4)60.4 (13.0)NR25.431.2NR65.273.4NR20.338.2NRNRNRNR1211.5NR24.822.5NR118.3NR5.95.3NRBavaria/1995 7NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRBonser/2002 8NR635842.942.9NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRCaimmi/1998 9NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRCampbell-Lloyd/2010 10NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRCefarelli/2017 11NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRCoselli/1997 12NRNRNRNRNRNRNR64.571.4NRNRNRNR24.127NR4.111.1NR62.458.7NR916.4NR41.441.8Di Eusanio/2003 1361.5NR6336.7NR32.523NR13.3NRNRNRNRNRNR4NR3NRNRNR6.8NR5.55.5NR12.5Di Mauro/2012 14NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRDong/2002 15NR48.5 +/- 11.450.3 +/- 11.7NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNREhrlich/1999 16NR58 (14)61 (13)NR3729NR9180NRNRNRNRNRNRNRNRNRNRNRNRNR40NR2634.5Forteza/2009 17NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRGanapathi/2014 1850.750.9NR37.542.5NR8269NR2.53.8NR135NR6.313.8NR37.531.3NR1.33.4NR2021.3NRGuan/2004 19NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRHagl/2001 20NRNRNRNRNRNR8072.262.7NRNRNRNRNRNRNRNRNRNRNRNRNRNRNR27.333.314.5Halkos/2009 2157.8+/-14.1NR54.5 +/- 13.930.2NR24.279NR77.35.6NR10.6NRNRNR12.7NR10.6NRNRNR10.2NR13.630.2NR31.8Han/2007 22NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRHarrington/2004 2367NR6040NR36.4NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRHata/2018 24NR68.5 +/-12.166.9 +/- 14.0NR40.444.6NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNR1.810NR78.5Higgins/2012 25NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRImmer/2008 2663NR60.929.4NR25.869.4NR69.8NRNRNRNRNRNRNRNRNRNRNRNRNRNRNR10NR9Kamenskaya/2015 2748.1NR4930NR32.33NR6NRNRNR10.3NR6.83NR3NRNRNRNRNRNRNRNRNRKamenskaya/2017 2852NR54.224.1NR20.779.3NR86.2NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRKamiya/2007 2959.6 +/- 11.9 NR60.9 +/- 11.4 22.6NR22.7NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRKaneda/2005 3068.667.3NR4758.8NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRKaneko/2014 3161.6 +/- 13.364.4 +/- 13.061.1 +/- 13.928.132.132.866.761.56318.421.837.6NRNRNR7.97.710.9NRNRNR7.92.63.6NRNRNRKazui/1989 3264.5 +/- 8.4NR56.5 +/- 7.127.27NR60NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNR9NR10Kitamura/1995 33NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRKrahenbuhl/2010 34NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRKruger/2012 3560.7NR59.839.9NR35.8NRNRNRNRNRNRNRNRNRNRNRNRNRNRNR19.6NR21.4NRNRNRLeMaire/2001 36NR6359NR3617NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRMatalanis/2002 3766.562.764.2830.428.6NRNRNR168.714.3241321.4NRNRNRNRNRNR248.77.1NRNRNRMilewski/2010 3864.159.9NR36.231.5NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNR13.811.7NR21.324.6NRMisfeld/2012 396362 +/- 1462 +/- 1535.925.538.2NRNRNR73.782.476.44.97.87.713.29.810.5NRNRNR6.39.85.5NRNRNRMishra/2009 40NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRMoon/2002 41NR64 +/- 1458 +/-18 NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNR814NRNRNAMüller/2004 4266646233.35058.3NRNRNRNRNRNRNRNRNRNRNRNRNRNRNR00.0516.7NRNRNRNeri/2004 4359.969.968.1322734.8NRNRNRNRNRNR2431.5132815.713282139.102130.4NRNRNRNiinami/2003 44NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNROkada/2015 45NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNROkita/2001 4667.669.1NR16.720NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNR06.7NRNRNRNROkita/2015 4770.5 +/- 10.168.3 +/- 11.6NR27.528NR85.884.1NRNRNRNR5.55.4NR14.413NR61.252.8NR14.711.8NRNRNRNRParamythiotis/2011 48NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRPerreas/2016 4961.3 +/- 11.462.8 +/- 13.1NA2335NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRSafi/2010 50NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRSchachner/2004 51NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRSinatra/2001 5258.461.759.134.838.9NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRStamou/2016 53586259NRNRNR79.876.474.5NRNRNRNRNRNR7.15.58.2NRNRNR4.89.19.8NRNRNRStevens/2009 54NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRStrauch/2005 5562NR6033NR42NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRSueda/1992 566268NR2528.6NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRSundt/2008 57647165495140777974NRNRNRNRNRNR928NRNRNR11410199Svensson/2001 58NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNR1NRNRNRNRSvensson/2015 595858NR3445NR7785NR116.7NR2020NRNRNRNR6363NR9.817NRNRNRNRTan/2003 60NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRTokuda/2014 6169.668.2NR58.657.1NR78.278.3NR12.88.5NR1.81.5NR5.87.4NR34.737.5NR13.513.6NRNRNRNRUsui/1999 6259.561.1NR4444NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNR129NR57NRVallabhajosyula/2014 636660NR3536NR6576NR1116NR1311NR1111NR2116NR45NR96NRWiedemann/2012 64625660313829748890NRNRNR92725NRNRNRNRNRNR398111616Williams/2012 6561.559.2NR37.531NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNR250NR253.5NRWong/1999 66NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRZierer/2007 67NR63 +/- 15 63 +/- 15 NR4535NR7378NRNRNRNRNRNRNR412NR5560NR1112NR1826Zierer/2005 686255NR26.350NR63.233.3NRNRNRNRNRNRNRNRNRNRNRNRNR7.95.5NRNRNRNRCVA; cerebrovascular accident, NR: not reported, SD: standard deviationACP: antegrade cerebral perfusion; RCP: retrograde cerebral perfusion; DHCA: deep hypothermic circulatory arrestSupplementary Table 3. Summary of critical appraisal of included observational studies using the Newcastle-Ottawa Quality Assessment Scale for Cohort StudiesAuthor Year?SelectionComparabilityOutcomeAhn/1997 1********Akashi/2000 2********Alamanni/1995 3********Apaydin/2009 4********Apostolakis/2008 5********Arnaoutakis/2017 6********Bavaria/1995 7***-***Bonser/2002 8NANANACaimmi/1998 9****-***Campbell-Lloyd/2010 10********Cefarelli/2017 11********Coselli/1997 12****-***Di Eusanio/2003 13********Di Mauro/2012 14********Dong/2002 15****-***Ehrlich/1999 16********Forteza/2009 17********Ganapathi/2014 18********Guan/2004 19****-***Hagl/2001 20********Halkos/2009 21********Han/2007 22****-***Harrington/2004 23NANANAHata/2018 24****-***Higgins/2012 25****-***Immer/2008 26****-***Kamenskaya/2015 27NANANAKamenskaya/2017 28NANANAKamiya/2007 29****-***Kaneda/2005 30****-***Kaneko/2014 31********Kazui/1989 32****-***Kitamura/1995 33****-***Krahenbuhl/2010 34****-***Kruger/2012 35********LeMaire/2001 36****-***Matalanis/2002 37********Milewski/2010 38********Misfeld/2012 39********Mishra/2009 40****-***Moon/2002 41********Müller/2004 42****-***Neri/2004 43****-***Niinami/2003 44****-***Okada/2015 45********Okita/2001 46****-***Okita/2015 47*********Paramythiotis/2011 48********Perreas/2016 49*********Safi/2010 50********Schachner/2004 51****-***Sinatra/2001 52********Stamou/2016 53********Stevens/2009 54********Strauch/2005 55****-***Sueda/1992 56****-***Sundt/2008 57********Svensson/2001 58NANANASvensson/2015 59NANANATan/2003 60********Tokuda/2014 61*********Usui/1999 62********Vallabhajosyula/2014 63****-***Wiedemann/2012 64********Williams/2012 65****-***Wong/1999 66********Zierer/2007 67****-***Zierer/2005 68********Selection?1)????????Representativeness of intervention cohort - a) truly representative of the average in the community *; b) somewhat representative of the average; c) only selected group of users; d) no description of the derivation of the cohort.2)????????Selection of non-intervention cohort – a) drawn from same community as intervention cohort*; b) drawn from a different source; c) no description of the derivation of the non-exposed cohort.3)????????Ascertainment of exposure - a) secure record*; b) structured interview*; c) written self-report; d) no description.4)????????Demonstration that outcome of interest was not present at start of study - a) yes*; b) parability?1)???????Comparability of cohorts on the basis of the design or analysis - a) study controls for age, and gender*; b) study controls for any additional factor*.Outcome?1)???????Assessment of outcome - a) independent blind assessment*;?b) record linkage*;?c) self-report; d) no description.2)???????Was follow-up long enough for outcomes to occur - a) yes*; b) no3)???????Adequacy of follow up of cohorts - a) complete follow up*;?b) subjects lost to follow up unlikely to introduce bias - < 20 % lost follow up*;?c) follow up rate < 80% and no description of those lost; d) no statement.Supplementary Table 4. The Cochrane Collaboration’s tool for assessing risk of bias in randomized trials.RANDOM SEQUENCE GENERATIONALLOCATION CONCEALMENTBLINDING OF PARTICIPANTS BLINDING OF OUTCOME ASSESSMENTINCOMPLETE OUTCOME DATASELECTIVE REPORTINGOTHER SOURCES OF BIASIV Milrinone StudiesBonser/2002 8+???++?Harrington/2004 23+++?++?Kamenskaya/2015 27+???++?Kamenskaya/2017 28+++?++?Svensson/2001 58+???++?Svensson/2015 59+++?++?+Low Risk ?Uncertain -High Risk Supplementary Table 5. Grading of recommendations, assessment, development, and evaluation (GRADE) estimates of effects, credible intervals, and certainty of evidence. Population: Adult Cardiac Surgery PatientsInterventions: ANTEGRADE CEREBRAL PERFUSION, RETROGRADE CEREBRAL PERFUSIONComparator (reference): DEEP HYPOTHERMIC CIRCULATORY ARRESTSetting: InpatientsOutcome: Post-operative strokeTotal Studies: 63Total Participants: 25973Relative Effect*(95%CrI)Anticipated Absolute Effect** (95%CrI)Certainty ofEvidence***Ranking****Interpretationof FindingsWithoutInterventionWithInterventionDifferenceANTEGRADE CEREBRAL PERFUSION (31 observational studies, 2 RCTs; 3548 matched/adjusted/randomized participants in the ACP arm)0.51(0.62-0.75)Network estimate Table109 per 100081 per 1,00028 per 1000 fewer⊕⊕⊕⊕High0.8883Definitely superiorRETROGRADE CEREBRAL PERFUSION(30 observational studies, 2 RCTs; 3014 matched/adjusted participants in the RCP arm)0.54(0.66-0.82)Network estimate109 per 100064 per 100045 per 1000 fewer⊕⊕⊕ModerateDue to publication bias0.6116Probably superiorDEEP HYPOTHERMIC CIRCULATORY ARRESTReference comparatorNot estimableNot estimableNot estimableReference comparator0.0000Not estimableOutcome: Operative mortalityTotal Studies: 59Total Participants: 23478Relative Effect*(95%CrI)Anticipated Absolute Effect**Certainty ofEvidence***Ranking****Interpretationof FindingsWithoutInterventionWithInterventionDifferenceANTEGRADE CEREBRAL PERFUSION (27 observational studies, 2 RCTs; 3187 matched/adjusted/randomized participants in the ACP arm)0.51(0.63-0.76)Network estimate148 per 100065 per 100083 per 1000fewer⊕⊕⊕⊕High0.5903Definitely superiorRETROGRADE CEREBRAL PERFUSION (24 observational studies, 2RCTs; 1410 matched/adjusted/randomized participants in the RCP arm)0.45(0.57-0.71)Network estimate148 per 100066 per 100082 per 1000fewer⊕⊕⊕⊕High0.9097Definitely superiorDEEP HYPOTHERMIC CIRCULATORY ARRESTReference comparatorNot estimableNot estimableNot estimableReference comparator0.0000Not estimableOutcome: Post-operative transient neurological deficitsTotal Studies: 1Total Participants: 4128Relative Effect*(95%CrI)Anticipated Absolute Effect**Certainty ofEvidence***Ranking****Interpretationof FindingsWithoutInterventionWithInterventionDifferenceANTEGRADE CEREBRAL PERFUSION (no direct evidence)0.78(1.03-1.35)Network estimate99 per 100052 per 100047 per 1000 fewer⊕⊕⊕ModerateDue to indirectness0.6863Probably superiorRETROGRADE CEREBRAL PERFUSION (no direct evidence)0.93(1.27-1.74)Network estimate99 per 100061 per 100038 per 1000 fewer⊕⊕⊕ModerateDue to indirectness0.0630Probably superiorDEEP HYPOTHERMIC CIRCULATORY ARRESTReference comparatorNot estimableNot estimableNot estimableReference comparator0.7507Not estimableOutcome: Post-operative myocardial infarctionTotal Studies: 5Total Participants: 1559Relative Effect*(95%CrI)Anticipated Absolute Effect** Certainty ofEvidence***Ranking****Interpretationof FindingsWithoutInterventionWithInterventionDifferenceANTEGRADE CEREBRAL PERFUSION (1 observational study, 1 RCT; 190 matched/adjusted/randomized participants in the ACP arm)0.56(1.38-3.39)Network estimate43 per 100045 per 10002 per 1000more⊕⊕⊕⊕High0.1389Definitely inferiorRETROGRADE CEREBRAL PERFUSION (no direct evidence)0.13(0.51-2.04)Network estimate43 per 10007 per 100036 per 1000fewer⊕⊕⊕ModerateDue to indirectness0.8967Probably superiorDEEP HYPOTHERMIC CIRCULATORY ARRESTReference comparatorNot estimableNot estimableNot estimableReference comparator0.4644Not estimableOutcome: Respiratory complicationsTotal Studies: 11Total Participants: 2588Relative Effect*(95%CI)Anticipated Absolute Effect** Certainty ofEvidence***Ranking****Interpretationof FindingsWithoutInterventionWithInterventionDifferenceANTEGRADE CEREBRAL PERFUSION (6 observational studies, 1 RCT; 809 matched/adjusted/randomized participants in the ACP arm)0.67(0.89-1.18)Network estimate241 per 1000289 per 100048 per 1000more⊕⊕⊕⊕High0.8077Probably superiorRETROGRADE CEREBRAL PERFUSION (5 studies; 226 matched/adjusted participants in the RCP arm)0.72(0.99-1.35)Network estimate241 per 1000259 per 100018 per 1000more⊕⊕⊕ModerateDue to inconsistency0.3532Probably inferiorDEEP HYPOTHERMIC CIRCULATORY ARRESTReference comparatorNot estimableNot estimableNot estimableReference comparator0.3391Not estimableOutcome: Renal failureTotal Studies: 19Total Participants: 9065Relative Effect*(95%CI)Anticipated Absolute Effect** Certainty ofEvidence***Ranking****Interpretationof FindingsWithoutInterventionWithInterventionDifferenceANTEGRADE CEREBRAL PERFUSION (8 observational studies, 1 RCT; 978 matched/adjusted/randomized participants in the ACP arm)0.56(0.87-1.35)Network estimate104 per 100066 per 100038 per 1000fewer⊕⊕⊕⊕High0.6718Probably superiorRETROGRADE CEREBRAL PERFUSION (7 studies; 469 matched/adjusted participants in the RCP arm)0.55(0.92-1.54)Network estimate104 per 100078 per 100026 per 1000fewer⊕⊕⊕⊕High0.5054Probably superiorDEEP HYPOTHERMIC CIRCULATORY ARRESTReference comparatorNot estimableNot estimableNot estimableReference comparator0.3228Not estimable*Network meta-analysis estimates are reported as odds ratio (OR) and confidence intervals (CI). **Anticipated absolute effect compares two risks by calculating the difference between the risk of the intervention group and the risk of the control group. CrI, credible intervals.*** The difference between direct and indirect estimates was considered as an estimate of inconsistency with the null hypothesis that consistency between the direct and indirect evidence exists, and in case of presence of a statistically significant difference between the direct and indirect evidence comparison (p<0.05), rejection of the null hypothesis will be done. In case of inconsistency, net heat plot was done to assess the source of inconsistency.**** Rank statistics is defined as the probabilities that a treatment out of n treatments in a network meta-analysis, is the best, the second, the third and so on until the last effective treatment.Supplementary Table 6. Definition of outcomes in included studiesStudy/YearPost-operative strokeTransient neurological deficitRespiratory complicationsRenal complicationsAhn/1997 1Stroke, brain death, coma, or hemiplegiaSlow awaking or aphasiaPulmonary embolism-Akashi/2000 2StrokeSow awaking without abnormal computed tomography (CT) findings--Alamanni/1995 3Coma, hemiplegiaSlow awaking, glosso-pharyngeal paresis, hemiparesis--Apaydin/2009 4Stroketransient confusion, agitation, lethargy, or obtundation not associated with stroke--Apostolakis/2008 5Hemiparesis, monoplegia, hemiplegia, paraplegia, comaConfusion, lethargy, psychosis, parkinsonism, choreoathetosis, seizurespneumonia, acuterespiratory distress syndrome (ARDS), or simple atelectasisRenal failureArnaoutakis/2017 6Stroke--Kidney Disease:Improving Global Outcomes (KDIGO) acute Kidney injuryBavaria/1995 7Stroke---Bonser/2002 8Sensory loss in cranial nerve functionObtundation--Caimmi/1998 9Permanent neurologic deficitTransient neurologic deficitRespiratory failureRenal failureCampbell-Lloyd/2010 10----Cefarelli/2017 11Stroke, coma, or lesions evidenced in CTAgitation, delirium, confusion, Parkinsonism, prolonged obtundation--Coselli/1997 12Stroke---Di Eusanio/2003 13Stroke or comaPostoperative confusion, agitation, delirium, prolonged obtundation, or transient parkinsonism-Postoperative dialysisDi Mauro/2012 14Stroketemporary neurological dysfunction (TND), defined by means of clinical signs with negative CT scan or magnetic resonance imaging (MRI)--Dong/2002 15Permanent neurological complicationTemporary neurological deficiencyEhrlich/1999 16Permanent cerebral complications: stroke, globalConfusion, agitation,or transient delirium-Renal failureForteza/2009 17Acute lesion in cranial CT and or persistent neurologicaldeficitAgitation, confusion, delirium,amnesia, postoperative Parkinson--Ganapathi/2014 18StrokeTransient mental status change, including delirium or disorientation--Guan/2004 19Permanent neurological complicationsProlonged postoperative confusion, agitation, or transient delirium--Hagl/2001 20-Temporary neurologic dysfunction--Halkos/2009 21New and permanent focal neurologicdeficit with or without evidence on imaging confirmed by a neurologistPostoperative confusion, delirium, obtundation, or transient focal deficits (resolution within 24 hours) with negative imagingARDS, pneumonia, pulmonary embolismRenal failureHan/2007 22-Temporary neurological dysfunction--Harrington/2004 23StrokeObtundation, temporary visual deficit, confusionHata/2018 24Permanent brain damageTemporary neurological dysfunctionPneumoniaRenal failureHiggins/2012 25Stroke---Immer/2008 26Postoperative permanent neurologic dysfunctionTransient ischemic attack, prolonged ischemic neurologic deficit--Kamenskaya/2015 27Focal neurological deficit persisting >24 hoursEncephalopathy--Kamenskaya/2017 28StrokeEncephalopathyPulmonary insufficiencyRenal insufficiencyKamiya/2007 29StrokeTransient neurological dysfunction--Kaneda/2005 30Neurological dysfunction continuing until discharge or led to death---Kaneko/2014 31StrokeTransient neuro deficit was defined as focal neurologic deficit with normal cerebral imaging and resolving in-Renal failureKazui/1989 32Permanent neurologic complicationConvulsionsPulmonary failureRenal failureKitamura/1995 33Stroke---Krahenbuhl/2010 34Persistent neurological deficitTransient neurological dysfunction--Kruger/2012 35Permanent neurological deficits that were focal (stroke) or global (parkinsonism, coma, gait disturbance) in nature and persisting at discharge from the hospital---LeMaire/2001 36StrokeSeizure, severe encephalopathy.--Matalanis/2002 37StrokeMild Intellectual disturbance, confusion, disorientation, or memory Disturbance--Milewski/2010 38Permanent neurologic deficitTemporary neurologic deficit--Misfeld/2012 39StrokeReversible deficitsRespiratory failureRenal failureMishra/2009 40StrokeTemporary deficit with normal imaging--Moon/2002 41Stroke, diffuse comaProlonged postoperative confusion, agitation, or transient delirium or ischemic deficits--Müller/2004 42Stroke---Neri/2004 43Stroke and permanent hemiplegiaAgitation or obtundationNiinami/2003 44Stroke-Respiratory failureRenal failureOkada/2015 45Stroke---Okita/2001 46StrokeInsomnia, restlessness, anxiety, euphoria, strange facial, appearance, unexplained complaints, manic depressive, disorientation, repetition, trying to remove intravenous or other lines and rejection of treatment, hallucination, wandering, struggling, persecution, maniaRespiratory complicationsRenal complicationsOkita/2015 47Stroke persisting more than 72 hoursNeurologic dysfunction that recovered completely within 72 hoursProlonged ventilation > 24 hours, pneumoniaRenal failure requiring dialysisParamythiotis/2011 48stroke---Perreas/2016 49Permanent neurological dysfunctionTemporary neurological dysfunction--Safi/2010 50Gross focal neurologic brain injury confirmed on CT scanning or MRI---Schachner/2004 51Stroke---Sinatra/2001 52Permanent neurological deficitConfusion, delayed awakening--Stamou/2016 53Stroke-Prolonged ventilationRequiring hemodialysisStevens/2009 54----Strauch/2005 55StrokeConditions that disappeared by time of dischargeRespiratory failureRenal failureSueda/1992 56-Delayed Awakening--Sundt/2008 57Cerebrovascular accidentProlonged ventilationRenal failureSvensson/2001 58-Temporary neurological deficit recovered on 6-month visit--Svensson/2015 59Brain imaging changes including (stroke + neurocognitive decline + visual symptoms)Seizures, delirium, peripheral twitching with no imaging changes--Tan/2003 60Stroke---Tokuda/2014 61StrokeTransient neurological dysfunctionProlonged ventilationDe novo hemodialysisUsui/1999 62StrokeNeurologic deficits not present on head CT--Vallabhajosyula/2014 63Stroke defined as new braininjury recorded clinically or radiographicallyTransient ischemic attackProlonged ventilationDoubling of the creatinine value during the in-hospital stay or the new need to start hemodialysis.Wiedemann/2012 64Central or peripheral neurologic deficit present at time of discharge from hospitalTransient ischemic attack-Renal failure requiring hemodialysisWilliams/2012 65Cerebrovascular accident occurring in < 24 hours post-operatively---Wong/1999 66Stroke defined as clinical finding of a new permanent neurological deficit and/or lesion on CT scans.---Zierer/2007 67Permanent neurological deficit: focal or globalDeliriums that recovered on discharge--Zierer/2005 68Focal (stroke) or global (coma) permanent neurological dysfunctionMotor deficit, confusion, agitation, delirium resolved on discharge and not seen on imaging--Supplementary Table 7. Outcomes summary of the meta-analyses. ACP: Antegrade cerebral perfusion, RCP: retrograde cerebral perfusion, DHCA: deep hypothermic circulatory arrest.Post-operative outcomesArmStudiesOR (95% confidence interval), P-valueHeterogeneity (I2, P-value)Stroke ACP vs DHCA350.68 [0.57; 0.82], P< 0.00012.3%, P=0.43RCP vs DHCA330.62 [0.47; 0.83], P=0.00118.9%, P=0.17ACP vs RCP350.92 [0.80; 1.05], P=0.200.4%, P=0.46Operative mortality ACP vs DHCA320.66 [0.56; 0.78], P< 0.00010.0%, P=0.50RCP vs DHCA280.51 [0.35; 0.73], P=0.000240.7%, P=0.01ACP vs RCP340.99 [0.86; 1.16], P=0.990.0%, P=0.53Transient neurological deficitsACP vs DHCA261.05 [0.72; 1.54], P=0.8053.0%, P<0.001RCP vs DHCA221.39 [0.99; 1.95], P=0.060.0%, P=0.77ACP vs RCP260.88 [0.74; 1.04], P=0.140.0%, P=0.57Myocardial infarctionACP vs DHCA31.41 [0.57; 3.46], P=0.460.0%, P=0.85RCP vs DHCA10.39 [0.01; 11.74], P=0.59Not availableACP vs RCP42.74 [0.90; 8.35], P=0.080.0%, P=0.42Respiratory complications ACP vs DHCA80.83 [0.62; 1.11], P=0.2119.9%, P=0.27RCP vs DHCA51.35 [0.95; 1.93], P=0.090.0%, P=0.61ACP vs RCP110.93 [0.75; 1.14], P=0.4652.9%, P=0.02Renal failure ACP vs DHCA120.94 [0.72; 1.23], P=0.640.0%, P=0.58RCP vs DHCA91.01 [0.68; 1.52], P=0.9417.7%, P=0.29ACP vs RCP151.05 [0.90; 1.22], P=0.520.0%, P=0.87Supplementary Table 8. Network plot of eligible comparisons of cerebral perfusion strategies for primary outcomes and league tables for the network meta-analysis showing odds ratio (OR) and 95% confidence intervals for different outcomes among the different treatment groups in random effect models. In the network plots, circles represent each intervention as a node and lines represent direct comparisons. The sizes of circles are proportional the number of patients receiving each treatment, and the width of the lines indicate the number of studies comparing every pair of treatment. The league tables are to be read horizontally, for example, antegrade cerebral perfusion (ACP) is associated with lower post-operative stroke compared to deep hypothermic circulatory arrest (DHCA) (OR 0.62 [95%CI 0.51; 0.75]) (bold font). ACP: Antegrade cerebral perfusion, RCP: retrograde cerebral perfusion, DHCA: deep hypothermic circulatory arrest.Post-operative stroke League TableDHCA 1.62 [1.34; 1.96] 1.51 [1.22; 1.87]0.62 [0.51; 0.75] ACP 0.93 [0.77; 1.12]0.66 [0.54; 0.82] 1.08 [0.89; 1.30] RCPOperative mortalityDHCA 1.60 [1.31; 1.95] 1.77 [1.40; 2.23]0.63 [0.51; 0.76] ACP 1.11 [0.89; 1.37]0.57 [0.45; 0.71] 0.90 [0.73; 1.12] RCPPost-operative transient neurological deficitsDHCA 0.98 [0.74; 1.28] 0.79 [0.57; 1.08] 1.03 [0.78; 1.35] ACP 0.81 [0.62; 1.05] 1.27 [0.93; 1.74] 1.24 [0.95; 1.62] RCPPost-operative myocardial infarctionDHCA 0.72 [0.29; 1.78] 1.97 [0.49; 7.94] 1.38 [0.56; 3.39] ACP 2.73 [0.91; 8.20] 0.51 [0.13; 2.04] 0.37 [0.12; 1.10] RCPRespiratory complicationsDHCA 1.12 [0.84; 1.49] 1.01 [0.74; 1.39] 0.89 [0.67; 1.18] ACP 0.90 [0.74; 1.11] 0.99 [0.72; 1.35] 1.11 [0.90; 1.36] RCPRenal failureDHCA 1.15 [0.74; 1.78] 1.08 [0.65; 1.81]0.87 [0.56; 1.35] ACP 0.94 [0.63; 1.42]0.92 [0.55; 1.54] 1.06 [0.70; 1.59] RCPSupplementary Table 9. Rank scores with probability ranks of different treatment groups (antegrade cerebral perfusion [ACP], retrograde cerebral perfusion [RCP], and deep hypothermic circulatory arrest [DHCA]). Ranks closest to 1 indicate the probability that the treatment group leads to greatest reduction in the relevant adverse outcome.Post-operative stroke P-score ACP 0.8883RCP 0.6116DHCA 0.0000Operative mortality P-scoreRCP 0.9097ACP 0.5903DHCA 0.0000Post-operative transient neurological deficits P-scoreDHCA 0.7507ACP 0.6863RCP 0.0630Post-operative myocardial infarction P-scoreRCP 0.8967DHCA 0.4644ACP 0.1389Respiratory complications P-scoreACP 0.8077RCP 0.3532DHCA 0.3391Renal failure P-scoreACP 0.6718RCP 0.5054DHCA 0.3228Supplementary Table 10. Netsplit for different treatment groups (antegrade cerebral perfusion [ACP], retrograde cerebral perfusion [RCP], and deep hypothermic circulatory arrest [DHCA]) in different outcomes.Post-operative stroke comparison k prop nma direct indir. Diff z p-value ACP:DHCA 35 0.83 -0.48 -0.40 -0.90 0.50 1.91 0.0567 ACP:RCP 35 0.87 -0.07 -0.15 0.43 -0.58 -2.04 0.0413 RCP:DHCA 33 0.69 -0.41 -0.44 -0.35 -0.10 -0.40 0.6856 Operative mortality comparison k prop nma direct indir. Diff z p-value ACP:DHCA 32 0.84 -0.47 -0.41 -0.77 0.36 1.28 0.2013 ACP:RCP 34 0.83 0.10 0.02 0.48 -0.46 -1.55 0.1203 RCP:DHCA 28 0.69 -0.57 -0.64 -0.41 -0.23 -0.90 0.3672Post-operative transient neurological deficits comparison k prop nma direct indir. Diff z p-value ACP:DHCA 26 0.84 0.02 0.05 -0.12 0.17 0.44 0.6595 ACP:RCP 26 0.87 -0.21 -0.17 -0.52 0.36 0.90 0.3668 RCP:DHCA 22 0.62 0.24 0.32 0.11 0.20 0.61 0.5389Post-operative myocardial infarction comparison k prop nma direct indir. Diff z p-value ACP:DHCA 3 1.00 0.32 0.34 -3.98 4.32 0.64 0.5246 ACP:RCP 4 0.98 1.00 1.01 0.68 0.33 0.08 0.9343 RCP:DHCA 1 0.17 -0.68 -0.93 -0.63 -0.30 -0.16 0.8759Respiratory complications comparison k prop nma direct indir. Diff z p-value ACP:DHCA 8 0.86 -0.11 -0.19 0.36 -0.55 -1.31 0.1914 ACP:RCP 12 0.98 -0.10 -0.07 -1.46 1.38 1.79 0.0737 RCP:DHCA 5 0.55 -0.01 0.29 -0.39 0.68 2.12 0.0338Renal failure comparison k prop nma direct indir. Diff z p-value ACP:DHCA 7 0.87 -0.14 -0.21 0.30 -0.51 -0.77 0.4408 ACP:RCP 8 0.94 -0.06 -0.04 -0.27 0.23 0.26 0.7944 RCP:DHCA 5 0.60 -0.08 0.09 -0.33 0.43 0.80 0.4251 Comparison: Treatment comparisonk: Number of studies providing direct evidenceprop: Direct evidence proportionnma: Estimated treatment effect (logOR) in network meta-analysisdirect: Estimated treatment effect (logOR) derived from direct evidenceindir.: Estimated treatment effect (logOR) derived from indirect evidenceDiff: Difference between direct and indirect treatment estimatesz: z-value of test for disagreement (direct versus indirect)p-value: p-value of test for disagreement (direct versus indirect)Supplementary Table 11. Quantifying heterogeneity/inconsistency, tests of heterogeneity (within designs) and inconsistency (between designs), and design-specific decomposition of within-designs Q statistic. In net heat plots, the areas of gray squares represent the relative contributions of designs listed in the columns to the network estimate of designs listed in the rows. The colors are associated with changes in inconsistency between direct and indirect evidence in designs listed in the rows after detaching the effect of designs listed in the columns. Blue colors indicate an increase, and warm colors indicate a decrease (the stronger the intensity of the color, the stronger the change). ACP: antegrade cerebral perfusion, RCP: retrograde cerebral perfusion, DHCA: deep hypothermic circulatory arrest.OutcomesQuantifying heterogeneity / inconsistency:Tests of heterogeneity (within designs) and inconsistency (between designs):Net heat plot to locate inconsistency in network meta-analysis 69 Post-operative stroketau^2 = 0.0425; I^2 = 14.1% Q d.f. p-valueTotal 94.31 81 0.1479Within designs 82.29 78 0.3480Between designs 12.02 3 0.0073Design-specific decomposition of within-designs Q statistic Design Q df p-value ACP:RCP 17.47 14 0.2320 DHCA:ACP 17.53 14 0.2290 DHCA:RCP 9.72 12 0.6408 DHCA:ACP:RCP 37.58 38 0.4888Between-designs Q statistic after detaching of single designs Detached design Q df p-value ACP:RCP 11.80 2 0.0027 DHCA:ACP 11.94 2 0.0025 DHCA:RCP 0.70 2 0.7063 DHCA:ACP:RCP 7.66 1 0.0057Operative mortalitytau^2 = 0.0718; I^2 = 21.8% Q d.f. p-valueTotal 94.69 74 0.0529Within designs 85.20 71 0.1199Between designs 9.49 3 0.0235Design-specific decomposition of within-designs Q statistic Design Q df p-value ACP:RCP 14.96 15 0.4543 DHCA:ACP 9.51 13 0.7333 DHCA:RCP 20.93 9 0.0129 DHCA:ACP:RCP 39.80 34 0.2277Between-designs Q statistic after detaching of single designs Detached design Q df p-value ACP:RCP 8.38 2 0.0152 DHCA:ACP 9.44 2 0.0089 DHCA:RCP 0.43 2 0.8058 DHCA:ACP:RCP 6.28 1 0.0122Post-operative transient neurological deficitstau^2 = 0.1112; I^2 = 25% Q d.f. p-valueTotal 77.35 58 0.0456Within designs 58.01 55 0.3651Between designs 19.35 3 0.0002Design-specific decomposition of within-designs Q statistic Design Q df p-value ACP:RCP 8.97 11 0.6246 DHCA:ACP 12.27 11 0.3438 DHCA:RCP 5.95 7 0.5452 DHCA:ACP:RCP 30.81 26 0.2352Between-designs Q statistic after detaching of single designs Detached design Q df p-value ACP:RCP 19.09 2 < 0.0001 DHCA:ACP 4.39 2 0.1115 DHCA:RCP 18.43 2 < 0.0001 DHCA:ACP:RCP 0.25 1 0.6177Post-operative myocardial infarctiontau^2 = 0; I^2 = 0% Q d.f. p-valueTotal 2.75 5 0.7392Within designs 2.28 3 0.5154Between designs 0.46 2 0.7944Design-specific decomposition of within-designs Q statistic Design Q df p-value ACP:RCP 2.02 2 0.3651 DHCA:ACP 0.27 1 0.6037Between-designs Q statistic after detaching of single designs Detached design Q df p-value ACP:RCP 0.06 1 0.8137 DHCA:ACP 0.45 1 0.5007 DHCA:ACP:RCP 0.00 0 --Respiratory complicationstau^2 = 0.0392; I^2 = 40.8% Q d.f. p-valueTotal 32.08 19 0.0306Within designs 20.16 16 0.2130Between designs 11.91 3 0.0077Design-specific decomposition of within-designs Q statistic Design Q df p-value ACP:RCP 13.22 7 0.0670 DHCA:ACP 0.35 3 0.9507 DHCA:ACP:RCP 6.60 6 0.3595Between-designs Q statistic after detaching of single designs Detached design Q df p-value ACP:RCP 5.71 2 0.0575 DHCA:ACP 6.22 2 0.0446 DHCA:RCP 10.58 2 0.0050 DHCA:ACP:RCP 0.53 1 0.4676Renal failuretau^2 = 0.0759; I^2 = 20% Q d.f. p-valueTotal 17.49 14 0.2309Within designs 16.47 11 0.1246Between designs 1.02 3 0.7956Design-specific decomposition of within-designs Q statistic Design Q df p-value ACP:RCP 1.01 3 0.7982 DHCA:ACP 0.96 2 0.6190 DHCA:ACP:RCP 14.50 6 0.0245Between-designs Q statistic after detaching of single designs Detached design Q df p-value ACP:RCP 0.85 2 0.6526 DHCA:ACP 0.40 2 0.8172 DHCA:RCP 0.57 2 0.7510 DHCA:ACP:RCP 0.71 1 0.4000In net heat plots, the areas of gray squares represent the relative contributions of designs listed in the columns to the network estimate of designs listed in the rows. 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