title: Cerebrovascular reactivity predicts stroke in high-grade carotid artery disease.
abstract: OBJECTIVE
  To assess the usefulness of transcranial Doppler CO2 reactivity (CO2R) for prediction of ipsilateral ischemic stroke in carotid artery stenosis and occlusion with a meta-analysis of prospective studies based on individual patient data.
  
  
  METHODS
  We searched Medline, Biosis Previews, Science Citation Index, The Cochrane Library, and EMBASE for studies in which patients with severe carotid artery stenosis or occlusion underwent Doppler CO2R testing (inhalation of CO2 or breath-holding) and were prospectively followed for ipsilateral ischemic stroke. Individual data from 754 patients from 9 studies were included. We used percentage cerebral blood flow velocity increase (pCi) during hypercapnia as the primary CO2R measure, and defined impaired reactivity as pCi <20% increase.
  
  
  RESULTS
  In a multiple regression model, impaired CO2R was independently associated with an increased risk of ipsilateral ischemic stroke (hazard ratio [HR] 3.69; confidence interval [CI] 2.01, 6.77; p < 0.0001). Risk prediction was similar for recently symptomatic vs asymptomatic patients. Using continuous values of pCi, a significant association between decreasing pCi and increasing risk of ipsilateral stroke was found: HR of 1.64 (95% CI 1.33, 2.02; p < 0.0001) per 10% decrease in pCi. For patients with asymptomatic internal carotid artery stenosis only (n = 330), a comparable stroke risk prediction was found: increasing HR 1.95 (95% CI 1.26, 3.04; p = 0.003) per 10% decrease in pCi.
  
  
  CONCLUSIONS
  This analysis supports the usefulness of CO2R in risk prediction for patients with severe carotid artery stenosis or occlusion, both in recently symptomatic and asymptomatic patients. Further studies should evaluate whether treatment strategies in asymptomatic patients based on CO2R could improve patient outcomes.
authors.affiliation: From the Department of Neurology (M.R., A.H.) and the Institute of Medical Biometry and Statistics (G.S., E.M.), University of Freiburg, Germany; Basel Institute for Clinical Epidemiology and Biostatistics (M.B.), University Hospital Basel, Switzerland; the Department of Clinical Epidemiology and Biostatistics (M.B.), McMaster University, Hamilton, Canada; Neurology Unit (C.A., P.P., F.V.), Università Campus Bio-Medico of Rome, Italy; School of Public Health (A.K.), Imperial College London, UK; the Department of Neurology (N.M.B.), Tel Aviv Sourasky Medical Center and Tel Aviv University, Israel; Columbia University Medical Center (N.P., R.S.M.), Neurological Institute of New York; the Department of Neurology and Neurosurgery (C.J.M.K.), Brain Center Rudolf Magnus, University Medical Center Utrecht, the Netherlands; the Department of Experimental and Clinical Medicine (M.S.), Marche Polytechnic University, Ancona, Italy; and Clinical Neurosciences (H.S.M.), University of Cambridge, UK. matthias.reinhard@uniklinik-freiburg.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Reinhard
authors.affiliation: From the Department of Neurology (M.R., A.H.) and the Institute of Medical Biometry and Statistics (G.S., E.M.), University of Freiburg, Germany; Basel Institute for Clinical Epidemiology and Biostatistics (M.B.), University Hospital Basel, Switzerland; the Department of Clinical Epidemiology and Biostatistics (M.B.), McMaster University, Hamilton, Canada; Neurology Unit (C.A., P.P., F.V.), Università Campus Bio-Medico of Rome, Italy; School of Public Health (A.K.), Imperial College London, UK; the Department of Neurology (N.M.B.), Tel Aviv Sourasky Medical Center and Tel Aviv University, Israel; Columbia University Medical Center (N.P., R.S.M.), Neurological Institute of New York; the Department of Neurology and Neurosurgery (C.J.M.K.), Brain Center Rudolf Magnus, University Medical Center Utrecht, the Netherlands; the Department of Experimental and Clinical Medicine (M.S.), Marche Polytechnic University, Ancona, Italy; and Clinical Neurosciences (H.S.M.), University of Cambridge, UK.
authors.forename: Guido
authors.initials: G
authors.lastname: Schwarzer
authors.affiliation: From the Department of Neurology (M.R., A.H.) and the Institute of Medical Biometry and Statistics (G.S., E.M.), University of Freiburg, Germany; Basel Institute for Clinical Epidemiology and Biostatistics (M.B.), University Hospital Basel, Switzerland; the Department of Clinical Epidemiology and Biostatistics (M.B.), McMaster University, Hamilton, Canada; Neurology Unit (C.A., P.P., F.V.), Università Campus Bio-Medico of Rome, Italy; School of Public Health (A.K.), Imperial College London, UK; the Department of Neurology (N.M.B.), Tel Aviv Sourasky Medical Center and Tel Aviv University, Israel; Columbia University Medical Center (N.P., R.S.M.), Neurological Institute of New York; the Department of Neurology and Neurosurgery (C.J.M.K.), Brain Center Rudolf Magnus, University Medical Center Utrecht, the Netherlands; the Department of Experimental and Clinical Medicine (M.S.), Marche Polytechnic University, Ancona, Italy; and Clinical Neurosciences (H.S.M.), University of Cambridge, UK.
authors.forename: Matthias
authors.initials: M
authors.lastname: Briel
authors.affiliation: From the Department of Neurology (M.R., A.H.) and the Institute of Medical Biometry and Statistics (G.S., E.M.), University of Freiburg, Germany; Basel Institute for Clinical Epidemiology and Biostatistics (M.B.), University Hospital Basel, Switzerland; the Department of Clinical Epidemiology and Biostatistics (M.B.), McMaster University, Hamilton, Canada; Neurology Unit (C.A., P.P., F.V.), Università Campus Bio-Medico of Rome, Italy; School of Public Health (A.K.), Imperial College London, UK; the Department of Neurology (N.M.B.), Tel Aviv Sourasky Medical Center and Tel Aviv University, Israel; Columbia University Medical Center (N.P., R.S.M.), Neurological Institute of New York; the Department of Neurology and Neurosurgery (C.J.M.K.), Brain Center Rudolf Magnus, University Medical Center Utrecht, the Netherlands; the Department of Experimental and Clinical Medicine (M.S.), Marche Polytechnic University, Ancona, Italy; and Clinical Neurosciences (H.S.M.), University of Cambridge, UK.
authors.forename: Claudia
authors.initials: C
authors.lastname: Altamura
authors.affiliation: From the Department of Neurology (M.R., A.H.) and the Institute of Medical Biometry and Statistics (G.S., E.M.), University of Freiburg, Germany; Basel Institute for Clinical Epidemiology and Biostatistics (M.B.), University Hospital Basel, Switzerland; the Department of Clinical Epidemiology and Biostatistics (M.B.), McMaster University, Hamilton, Canada; Neurology Unit (C.A., P.P., F.V.), Università Campus Bio-Medico of Rome, Italy; School of Public Health (A.K.), Imperial College London, UK; the Department of Neurology (N.M.B.), Tel Aviv Sourasky Medical Center and Tel Aviv University, Israel; Columbia University Medical Center (N.P., R.S.M.), Neurological Institute of New York; the Department of Neurology and Neurosurgery (C.J.M.K.), Brain Center Rudolf Magnus, University Medical Center Utrecht, the Netherlands; the Department of Experimental and Clinical Medicine (M.S.), Marche Polytechnic University, Ancona, Italy; and Clinical Neurosciences (H.S.M.), University of Cambridge, UK.
authors.forename: Paola
authors.initials: P
authors.lastname: Palazzo
authors.affiliation: From the Department of Neurology (M.R., A.H.) and the Institute of Medical Biometry and Statistics (G.S., E.M.), University of Freiburg, Germany; Basel Institute for Clinical Epidemiology and Biostatistics (M.B.), University Hospital Basel, Switzerland; the Department of Clinical Epidemiology and Biostatistics (M.B.), McMaster University, Hamilton, Canada; Neurology Unit (C.A., P.P., F.V.), Università Campus Bio-Medico of Rome, Italy; School of Public Health (A.K.), Imperial College London, UK; the Department of Neurology (N.M.B.), Tel Aviv Sourasky Medical Center and Tel Aviv University, Israel; Columbia University Medical Center (N.P., R.S.M.), Neurological Institute of New York; the Department of Neurology and Neurosurgery (C.J.M.K.), Brain Center Rudolf Magnus, University Medical Center Utrecht, the Netherlands; the Department of Experimental and Clinical Medicine (M.S.), Marche Polytechnic University, Ancona, Italy; and Clinical Neurosciences (H.S.M.), University of Cambridge, UK.
authors.forename: Alice
authors.initials: A
authors.lastname: King
authors.affiliation: From the Department of Neurology (M.R., A.H.) and the Institute of Medical Biometry and Statistics (G.S., E.M.), University of Freiburg, Germany; Basel Institute for Clinical Epidemiology and Biostatistics (M.B.), University Hospital Basel, Switzerland; the Department of Clinical Epidemiology and Biostatistics (M.B.), McMaster University, Hamilton, Canada; Neurology Unit (C.A., P.P., F.V.), Università Campus Bio-Medico of Rome, Italy; School of Public Health (A.K.), Imperial College London, UK; the Department of Neurology (N.M.B.), Tel Aviv Sourasky Medical Center and Tel Aviv University, Israel; Columbia University Medical Center (N.P., R.S.M.), Neurological Institute of New York; the Department of Neurology and Neurosurgery (C.J.M.K.), Brain Center Rudolf Magnus, University Medical Center Utrecht, the Netherlands; the Department of Experimental and Clinical Medicine (M.S.), Marche Polytechnic University, Ancona, Italy; and Clinical Neurosciences (H.S.M.), University of Cambridge, UK.
authors.forename: Natan M
authors.initials: NM
authors.lastname: Bornstein
authors.affiliation: From the Department of Neurology (M.R., A.H.) and the Institute of Medical Biometry and Statistics (G.S., E.M.), University of Freiburg, Germany; Basel Institute for Clinical Epidemiology and Biostatistics (M.B.), University Hospital Basel, Switzerland; the Department of Clinical Epidemiology and Biostatistics (M.B.), McMaster University, Hamilton, Canada; Neurology Unit (C.A., P.P., F.V.), Università Campus Bio-Medico of Rome, Italy; School of Public Health (A.K.), Imperial College London, UK; the Department of Neurology (N.M.B.), Tel Aviv Sourasky Medical Center and Tel Aviv University, Israel; Columbia University Medical Center (N.P., R.S.M.), Neurological Institute of New York; the Department of Neurology and Neurosurgery (C.J.M.K.), Brain Center Rudolf Magnus, University Medical Center Utrecht, the Netherlands; the Department of Experimental and Clinical Medicine (M.S.), Marche Polytechnic University, Ancona, Italy; and Clinical Neurosciences (H.S.M.), University of Cambridge, UK.
authors.forename: Nils
authors.initials: N
authors.lastname: Petersen
authors.affiliation: From the Department of Neurology (M.R., A.H.) and the Institute of Medical Biometry and Statistics (G.S., E.M.), University of Freiburg, Germany; Basel Institute for Clinical Epidemiology and Biostatistics (M.B.), University Hospital Basel, Switzerland; the Department of Clinical Epidemiology and Biostatistics (M.B.), McMaster University, Hamilton, Canada; Neurology Unit (C.A., P.P., F.V.), Università Campus Bio-Medico of Rome, Italy; School of Public Health (A.K.), Imperial College London, UK; the Department of Neurology (N.M.B.), Tel Aviv Sourasky Medical Center and Tel Aviv University, Israel; Columbia University Medical Center (N.P., R.S.M.), Neurological Institute of New York; the Department of Neurology and Neurosurgery (C.J.M.K.), Brain Center Rudolf Magnus, University Medical Center Utrecht, the Netherlands; the Department of Experimental and Clinical Medicine (M.S.), Marche Polytechnic University, Ancona, Italy; and Clinical Neurosciences (H.S.M.), University of Cambridge, UK.
authors.forename: Edith
authors.initials: E
authors.lastname: Motschall
authors.affiliation: From the Department of Neurology (M.R., A.H.) and the Institute of Medical Biometry and Statistics (G.S., E.M.), University of Freiburg, Germany; Basel Institute for Clinical Epidemiology and Biostatistics (M.B.), University Hospital Basel, Switzerland; the Department of Clinical Epidemiology and Biostatistics (M.B.), McMaster University, Hamilton, Canada; Neurology Unit (C.A., P.P., F.V.), Università Campus Bio-Medico of Rome, Italy; School of Public Health (A.K.), Imperial College London, UK; the Department of Neurology (N.M.B.), Tel Aviv Sourasky Medical Center and Tel Aviv University, Israel; Columbia University Medical Center (N.P., R.S.M.), Neurological Institute of New York; the Department of Neurology and Neurosurgery (C.J.M.K.), Brain Center Rudolf Magnus, University Medical Center Utrecht, the Netherlands; the Department of Experimental and Clinical Medicine (M.S.), Marche Polytechnic University, Ancona, Italy; and Clinical Neurosciences (H.S.M.), University of Cambridge, UK.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hetzel
authors.affiliation: From the Department of Neurology (M.R., A.H.) and the Institute of Medical Biometry and Statistics (G.S., E.M.), University of Freiburg, Germany; Basel Institute for Clinical Epidemiology and Biostatistics (M.B.), University Hospital Basel, Switzerland; the Department of Clinical Epidemiology and Biostatistics (M.B.), McMaster University, Hamilton, Canada; Neurology Unit (C.A., P.P., F.V.), Università Campus Bio-Medico of Rome, Italy; School of Public Health (A.K.), Imperial College London, UK; the Department of Neurology (N.M.B.), Tel Aviv Sourasky Medical Center and Tel Aviv University, Israel; Columbia University Medical Center (N.P., R.S.M.), Neurological Institute of New York; the Department of Neurology and Neurosurgery (C.J.M.K.), Brain Center Rudolf Magnus, University Medical Center Utrecht, the Netherlands; the Department of Experimental and Clinical Medicine (M.S.), Marche Polytechnic University, Ancona, Italy; and Clinical Neurosciences (H.S.M.), University of Cambridge, UK.
authors.forename: Randolph S
authors.initials: RS
authors.lastname: Marshall
authors.affiliation: From the Department of Neurology (M.R., A.H.) and the Institute of Medical Biometry and Statistics (G.S., E.M.), University of Freiburg, Germany; Basel Institute for Clinical Epidemiology and Biostatistics (M.B.), University Hospital Basel, Switzerland; the Department of Clinical Epidemiology and Biostatistics (M.B.), McMaster University, Hamilton, Canada; Neurology Unit (C.A., P.P., F.V.), Università Campus Bio-Medico of Rome, Italy; School of Public Health (A.K.), Imperial College London, UK; the Department of Neurology (N.M.B.), Tel Aviv Sourasky Medical Center and Tel Aviv University, Israel; Columbia University Medical Center (N.P., R.S.M.), Neurological Institute of New York; the Department of Neurology and Neurosurgery (C.J.M.K.), Brain Center Rudolf Magnus, University Medical Center Utrecht, the Netherlands; the Department of Experimental and Clinical Medicine (M.S.), Marche Polytechnic University, Ancona, Italy; and Clinical Neurosciences (H.S.M.), University of Cambridge, UK.
authors.forename: Catharina J M
authors.initials: CJ
authors.lastname: Klijn
authors.affiliation: From the Department of Neurology (M.R., A.H.) and the Institute of Medical Biometry and Statistics (G.S., E.M.), University of Freiburg, Germany; Basel Institute for Clinical Epidemiology and Biostatistics (M.B.), University Hospital Basel, Switzerland; the Department of Clinical Epidemiology and Biostatistics (M.B.), McMaster University, Hamilton, Canada; Neurology Unit (C.A., P.P., F.V.), Università Campus Bio-Medico of Rome, Italy; School of Public Health (A.K.), Imperial College London, UK; the Department of Neurology (N.M.B.), Tel Aviv Sourasky Medical Center and Tel Aviv University, Israel; Columbia University Medical Center (N.P., R.S.M.), Neurological Institute of New York; the Department of Neurology and Neurosurgery (C.J.M.K.), Brain Center Rudolf Magnus, University Medical Center Utrecht, the Netherlands; the Department of Experimental and Clinical Medicine (M.S.), Marche Polytechnic University, Ancona, Italy; and Clinical Neurosciences (H.S.M.), University of Cambridge, UK.
authors.forename: Mauro
authors.initials: M
authors.lastname: Silvestrini
authors.affiliation: From the Department of Neurology (M.R., A.H.) and the Institute of Medical Biometry and Statistics (G.S., E.M.), University of Freiburg, Germany; Basel Institute for Clinical Epidemiology and Biostatistics (M.B.), University Hospital Basel, Switzerland; the Department of Clinical Epidemiology and Biostatistics (M.B.), McMaster University, Hamilton, Canada; Neurology Unit (C.A., P.P., F.V.), Università Campus Bio-Medico of Rome, Italy; School of Public Health (A.K.), Imperial College London, UK; the Department of Neurology (N.M.B.), Tel Aviv Sourasky Medical Center and Tel Aviv University, Israel; Columbia University Medical Center (N.P., R.S.M.), Neurological Institute of New York; the Department of Neurology and Neurosurgery (C.J.M.K.), Brain Center Rudolf Magnus, University Medical Center Utrecht, the Netherlands; the Department of Experimental and Clinical Medicine (M.S.), Marche Polytechnic University, Ancona, Italy; and Clinical Neurosciences (H.S.M.), University of Cambridge, UK.
authors.forename: Hugh S
authors.initials: HS
authors.lastname: Markus
authors.affiliation: From the Department of Neurology (M.R., A.H.) and the Institute of Medical Biometry and Statistics (G.S., E.M.), University of Freiburg, Germany; Basel Institute for Clinical Epidemiology and Biostatistics (M.B.), University Hospital Basel, Switzerland; the Department of Clinical Epidemiology and Biostatistics (M.B.), McMaster University, Hamilton, Canada; Neurology Unit (C.A., P.P., F.V.), Università Campus Bio-Medico of Rome, Italy; School of Public Health (A.K.), Imperial College London, UK; the Department of Neurology (N.M.B.), Tel Aviv Sourasky Medical Center and Tel Aviv University, Israel; Columbia University Medical Center (N.P., R.S.M.), Neurological Institute of New York; the Department of Neurology and Neurosurgery (C.J.M.K.), Brain Center Rudolf Magnus, University Medical Center Utrecht, the Netherlands; the Department of Experimental and Clinical Medicine (M.S.), Marche Polytechnic University, Ancona, Italy; and Clinical Neurosciences (H.S.M.), University of Cambridge, UK.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Vernieri
mesh_terms: D001783:Blood Flow Velocity; D002545:Brain Ischemia / Q000175:diagnosis / Q000000981:diagnostic imaging / Q000209:etiology / Q000503:physiopathology; D002245:Carbon Dioxide / Q000378:metabolism*; D002340:Carotid Artery Diseases / Q000150:complications* / Q000000981:diagnostic imaging* / Q000503:physiopathology; D016893:Carotid Stenosis; D002560:Cerebrovascular Circulation; D006801:Humans; D011379:Prognosis; D016016:Proportional Hazards Models; D012044:Regression Analysis; D018570:Risk Assessment / Q000379:methods; D012307:Risk Factors; D020521:Stroke / Q000175:diagnosis* / Q000000981:diagnostic imaging* / Q000209:etiology / Q000503:physiopathology; D013997:Time Factors; D017585:Ultrasonography, Doppler, Transcranial / Q000379:methods*
chemical_list: D002245:Carbon Dioxide