Clinical short communication| Volume 423, 117364, April 15, 2021

Prognostic significance of early pyrexia in acute intracerebral haemorrhage: The INTERACT2 study

  • Alejandra Malavera
    The George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, Australia
    Search for articles by this author
  • Shoujiang You
    The George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, Australia

    Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou, PR China
    Search for articles by this author
  • Danni Zheng
    The George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, Australia

    Discipline of Pharmacology, School of Medical Sciences, Faculty of Medicine and Health, Sydney, Australia
    Search for articles by this author
  • Candice Delcourt
    The George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, Australia

    Neurology Department, Royal Prince Alfred Hospital, Sydney Health Partners, Sydney, Australia
    Search for articles by this author
  • Craig S. Anderson
    Corresponding author at: The George Institute for Global Health, Level 5, 1 King Street, Newtown 2042, NSW, Australia.
    The George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, Australia

    The George Institute China at Peking University Health Science Center, Beijing, PR China

    Neurology Department, Royal Prince Alfred Hospital, Sydney Health Partners, Sydney, Australia
    Search for articles by this author
  • on behalf of the INTERACT2 Investigators
    Author Footnotes
    1 For a full list of INTERACT2 Investigators, see reference [11].
  • Author Footnotes
    1 For a full list of INTERACT2 Investigators, see reference [11].
Published:February 26, 2021DOI:


      • Elevated body temperature predicts worse outcomes after stroke.
      • Early pyrexia is associated with greater mortality and larger perihaematomal oedema in intracerebral haemorrhage.
      • Early pyrexia is associated with larger volume of perihaematomal oedema.



      Uncertainty exists over the prognostic significance of pyrexia in acute intracerebral haemorrhage (ICH). We aimed to determine the association of elevated body temperature with clinical and imaging outcomes among participants of the main Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT2).


      Post-hoc analyses of INTERACT2, an international open, blinded outcome assessed, randomised trial of 2839 patients with spontaneous ICH (<6 h of onset) and elevated systolic blood pressure (SBP, 150–220 mmHg) randomly assigned to intensive (SBP target <140 mmHg) or guideline-recommended (SBP target < 180 mmHg) BP management. Multivariable logistic regression was used to determine associations of elevated baseline body temperature (<37.5 vs. ≥37.5 °C) and 90-day clinical outcome defined on the modified Rankin scale (mRS). Analysis of covariance determined relations of body temperature and haematoma and perihaematomal oedema (PHE) volumes, at baseline and 24 h post-randomisation.


      Of 2792 participants with data available at admission, 39 (1.4%) patients had elevated body temperature ≥ 37.5 °C. Elevated body temperature was significantly associated with 90-day mortality (adjusted odds ratio 2.44; 95% confidence interval 1.02–5.82; P = .044) but not with major disability alone (mRS scores 3–5) and combination death or major disability (mRS scores 3–6). Elevated body temperature was also associated with larger PHE volume at baseline (10.89 vs. 3.14 cm3, P < .001;) and 24 h (12.43 vs 5.76 cm3, P = .018) but not with haematoma volumes at these time points.


      Early pyrexia in mild to moderate ICH is associated with greater mortality and larger PHE volume, suggesting an early inflammatory-mediated reaction.

      Clinical trial registration (NCT00716079).


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Journal of the Neurological Sciences
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Rincon F.
        • Mayer S.A.
        Clinical review: critical care management of spontaneous intracerebral hemorrhage.
        Crit. Care. 2008; 12: 237
        • Commichau C.
        • Scarmeas N.
        • Mayer S.A.
        Risk factors for fever in the neurologic intensive care unit.
        Neurology. 2003; 60: 837-841
        • Corbett D.
        • Thornhill J.
        Temperature modulation (hypothermic and hyperthermic conditions) and its influence on histological and behavioral outcomes following cerebral ischemia.
        Brain Pathol. 2000; 10: 145-152
        • Kim Y.
        • Busto R.
        • Dietrich W.D.
        • Kraydieh S.
        • Ginsberg M.D.
        Delayed postischemic hyperthermia in awake rats worsens the histopathological outcome of transient focal cerebral ischemia.
        Stroke. 1996; 27: 2274-2280
        • Busto R.
        • Dietrich W.D.
        • Globus M.Y.
        • Valdes I.
        • Scheinberg P.
        • Ginsberg M.D.
        Small differences in intraischemic brain temperature critically determine the extent of ischemic neuronal injury.
        J. Cereb. Blood Flow Metab. 1987; 7: 729-738
        • Schwarz S.
        • Hafner K.
        • Aschoff A.
        • Schwab S.
        Incidence and prognostic significance of fever following intracerebral hemorrhage.
        Neurology. 2000; 54: 354-361
        • Wang Y.
        • Lim L.L.
        • Levi C.
        • Heller R.F.
        • Fisher J.
        Influence of admission body temperature on stroke mortality.
        Stroke. 2000; 31: 404-409
        • Reith J.
        • Jorgensen H.S.
        • Pedersen P.M.
        • Nakayama H.
        • Raaschou H.O.
        • Jeppesen L.L.
        • Olsen T.S.
        Body temperature in acute stroke: relation to stroke severity, infarct size, mortality, and outcome.
        Lancet. 1996; 347: 422-425
        • Greer D.M.
        • Funk S.E.
        • Reaven N.L.
        • Ouzounelli M.
        • Uman G.C.
        Impact of fever on outcome in patients with stroke and neurologic injury: a comprehensive meta-analysis.
        Stroke. 2008; 39: 3029-3035
        • Urday S.
        • Kimberly W.T.
        • Beslow L.A.
        • Vortmeyer A.O.
        • Selim M.H.
        • Rosand J.
        • Simard J.M.
        • Sheth K.N.
        Targeting secondary injury in intracerebral haemorrhage—perihaematomal oedema.
        Nat. Rev. Neurol. 2015; 11: 111-122
        • Anderson C.S.
        • Heeley E.
        • Huang Y.
        • Wang J.
        • Stapf C.
        • Delcourt C.
        • Lindley R.
        • Robinson T.
        • Lavados P.
        • Neal B.
        • Hata J.
        • Arima H.
        • Parsons M.
        • Li Y.
        • Wang J.
        • Heritier S.
        • Li Q.
        • Woodward M.
        • Simes R.J.
        • Davis S.M.
        • Chalmers J.
        • Investigators I.
        Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage.
        N. Engl. J. Med. 2013; 368: 2355-2365
        • Bamford J.M.
        • Sandercock P.A.
        • Warlow C.P.
        • Slattery J.
        Interobserver agreement for the assessment of handicap in stroke patients.
        Stroke. 1989; 20: 828
        • Rincon F.
        • Lyden P.
        • Mayer S.A.
        Relationship between temperature, hematoma growth, and functional outcome after intracerebral hemorrhage.
        Neurocrit. Care. 2013; 18: 45-53
        • Allan V.
        • Ramagopalan S.V.
        • Mardekian J.
        • Jenkins A.
        • Li X.
        • Pan X.
        • Luo X.
        Propensity score matching and inverse probability of treatment weighting to address confounding by indication in comparative effectiveness research of oral anticoagulants.
        J. Comp. Eff. Res. 2020; 9: 603-614
        • Kollmar R.
        • Staykov D.
        • Dorfler A.
        • Schellinger P.D.
        • Schwab S.
        • Bardutzky J.
        Hypothermia reduces perihemorrhagic edema after intracerebral hemorrhage.
        Stroke. 2010; 41: 1684-1689
        • Aronowski J.
        • Zhao X.
        Molecular pathophysiology of cerebral hemorrhage: secondary brain injury.
        Stroke. 2011; 42: 1781-1786
        • Alexandrova M.L.
        • Danovska M.P.
        Serum C-reactive protein and lipid hydroperoxides in predicting short-term clinical outcome after spontaneous intracerebral hemorrhage.
        J. Clin. Neurosci. 2011; 18: 247-252
        • Gillow S.J.
        • Ouyang B.
        • Lee V.H.
        • John S.
        Factors associated with fever in intracerebral hemorrhage.
        J. Stroke Cerebrovasc. Dis. 2017; 26: 1204-1208
        • Azzimondi G.
        • Bassein L.
        • Nonino F.
        • Fiorani L.
        • Vignatelli L.
        • Re G.
        • D’Alessandro R.
        Fever in acute stroke worsens prognosis: a prospective study.
        Stroke. 1995; 26: 2040-2043
        • Hong J.M.
        • Lee J.S.
        • Song H.J.
        • Jeong H.S.
        • Choi H.A.
        • Lee K.
        Therapeutic hypothermia after recanalization in patients with acute ischemic stroke.
        Stroke. 2014; 45: 134-140
        • Balami J.S.
        • Buchan A.M.
        Complications of intracerebral haemorrhage.
        Lancet Neurol. 2012; 11: 101-118
        • Levine J.M.
        • Snider R.
        • Finkelstein D.
        • Gurol M.E.
        • Chanderraj R.
        • Smith E.E.
        • Greenberg S.M.
        • Rosand J.
        Early edema in warfarin-related intracerebral hemorrhage.
        Neurocrit. Care. 2007; 7: 58-63
        • Furie K.L.
        • Rosenberg R.
        • Thompson J.L.
        • Bauer K.
        • Mohr J.P.
        • Rosner B.
        • Sciacca R.
        • Barzegar S.
        • Thornell B.
        • Costigan T.
        • Kistler J.P.
        Thrombin generation in non-cardioembolic stroke subtypes: the hemostatic system activation study.
        Neurology. 2004; 63: 777-784
        • Campos F.
        • Sobrino T.
        • Vieites-Prado A.
        • Perez-Mato M.
        • Rodriguez-Yanez M.
        • Blanco M.
        • Castillo J.
        Hyperthermia in human ischemic and hemorrhagic stroke: similar outcome, different mechanisms.
        PLoS One. 2013; 8e78429
        • Belur P.K.
        • Chang J.J.
        • He S.
        • Emanuel B.A.
        • Mack W.J.
        Emerging experimental therapies for intracerebral hemorrhage: targeting mechanisms of secondary brain injury.
        Neurosurg. Focus. 2013; 34E9
        • Li N.
        • Liu Y.F.
        • Ma L.
        • Worthmann H.
        • Wang Y.L.
        • Wang Y.J.
        • Gao Y.P.
        • Raab P.
        • Dengler R.
        • Weissenborn K.
        • Zhao X.Q.
        Association of molecular markers with perihematomal edema and clinical outcome in intracerebral hemorrhage.
        Stroke. 2013; 44: 658-663
        • Fingas M.
        • Clark D.L.
        • Colbourne F.
        The effects of selective brain hypothermia on intracerebral hemorrhage in rats.
        Exp. Neurol. 2007; 208: 277-284
        • Volbers B.
        • Herrmann S.
        • Willfarth W.
        • Lucking H.
        • Kloska S.P.
        • Doerfler A.
        • Huttner H.B.
        • Kuramatsu J.B.
        • Schwab S.
        • Staykov D.
        Impact of hypothermia initiation and duration on perihemorrhagic edema evolution after intracerebral hemorrhage.
        Stroke. 2016; 47: 2249-2255
        • Lakhan S.E.
        • Pamplona F.
        Application of mild therapeutic hypothermia on stroke: a systematic review and meta-analysis.
        Stroke Res. Treat. 2012; 2012: 295906
        • Den Hertog H.M.
        • van der Worp H.B.
        • Tseng M.C.
        • Dippel D.W.
        Cooling therapy for acute stroke.
        Cochrane Database Syst. Rev. 2009; : CD001247
        • Hemphill III, J.C.
        • Greenberg S.M.
        • Anderson C.S.
        • Becker K.
        • Bendok B.R.
        • Cushman M.
        • Fung G.L.
        • Goldstein J.N.
        • Macdonald R.L.
        • Mitchell P.H.
        • Scott P.A.
        • Selim M.H.
        • Woo D.
        • C. American Heart Association Stroke
        • C. Council on
        • N. Stroke
        • C. Council on Clinical
        Guidelines for the Management of Spontaneous Intracerebral Hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.
        Stroke. 2015; 46: 2032-2060
        • Castillo J.
        • Davalos A.
        • Marrugat J.
        • Noya M.
        Timing for fever-related brain damage in acute ischemic stroke.
        Stroke. 1998; 29: 2455-2460
        • Austin P.C.
        • Stuart E.A.
        Moving towards best practice when using inverse probability of treatment weighting (IPTW) using the propensity score to estimate causal treatment effects in observational studies.
        Stat. Med. 2015; 34: 3661-3679
        • Dehkharghani S.
        • Bowen M.
        • Haussen D.C.
        • Gleason T.
        • Prater A.
        • Cai Q.
        • Kang J.
        • Nogueira R.G.
        Body temperature modulates infarction growth following endovascular reperfusion.
        AJNR Am. J. Neuroradiol. 2017; 38: 46-51
        • Christensen H.
        • Boysen G.
        Acceptable agreement between tympanic and rectal temperature in acute stroke patients.
        Int. J. Clin. Pract. 2002; 56: 82-84