Volume replacement is associated with a diminished osmolar effect of mannitol in patients with acute brain injury



      Animal experiments recently demonstrated that replacing urinary loses with crystalloid diminishes the therapeutic effect of mannitol by reducing the increase in osmolality. We aimed to investigate whether this effect is similarly seen in in brain-injured patients by studying the association between total body fluid balance (TBB) and the osmolar response to mannitol.


      We performed a retrospective cohort study of adult patients with acute brain injury between 2015 and 2021 who received ≥ 2 doses of mannitol within 8 hours and no intercurrent concentrated saline solution. We analyzed the association between the change in TBB (∆TBB) and change in osmolality (∆Osm) before and after mannitol in a linear model, both as univariate and after adjustment for common confounding factors.


      Of 6,145 patients who received mannitol, 155 patients met inclusion criteria (mean age 60 ± 17 years, 48% male, 83% white). The mean total mannitol dose was 2 ± 0.5 g/kg and the mean change in plasma osmolality was 7.9 ± 7.1 mOsm/kg. Each 1 L increase in ∆TBB was associated with a change of -1.1 mOsm/L in ∆Osm (95% CI [-2.2, -0.02], p = 0.045). The magnitude of association was similar to that of total mannitol dose and remained consistent in an adjusted model and after excluding outliers.


      In patients with acute brain injury, a positive TBB is associated with a diminished mannitol-induced increase in plasma osmolality. Future prospective studies are needed to confirm these findings and their influence on the therapeutic effect of mannitol.


      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 Stroke and Cerebrovascular Diseases
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Ropper AH.
        Hyperosmolar therapy for raised intracranial pressure.
        N Engl J Med. 2012; 367: 746-752
        • Diringer MN.
        New trends in hyperosmolar therapy?.
        Curr Opin Crit Care. 2013; 19: 77-82
        • Stahl WM.
        Effect of mannitol on the kidney: changes in intrarenal hemodynamics.
        N Engl J Med. 1965; 272: 382-386
        • Rudehill A
        • Gordon E
        • Ohman G
        • Lindqvist C
        • Andersson P.
        Pharmacokinetics and effects of mannitol on hemodynamics, blood and cerebrospinal fluid electrolytes, and osmolality during intracranial surgery.
        J Neurosurg Anesthesiol. 1993; 5: 4-12
        • Zornow M
        • Scheller M.
        Intraoperative Fluid Management During Craniotomy, Anesthesia and Neurosurgery.
        4th ed. Mosby, Philadelphia2001
        • Keyrouz SG
        • Dhar R
        • Diringer MN.
        Variation in osmotic response to sustained mannitol administration.
        Neurocrit Care. 2008; 9: 204-209
        • Gipstein RM
        • Boyle JD.
        Hypernatremia complicating prolonged mannitol diuresis.
        N Engl J Med. 1965; 272: 1116-1117
        • Gottschalk A
        • Toung TJK.
        Effects of volume replacement for urinary losses from mannitol diuresis on brain water in normal rats.
        Neurocrit Care. 2021; 35: 24-29
        • Diringer MN
        • Zazulia AR.
        Osmotic therapy: fact and fiction.
        Neurocrit Care. 2004; 1: 219-233
        • James HE.
        The effect of intravenous fluid replacement on the response to mannitol in experimental cerebral edema: an analysis of intracranial pressure, serum osmolality, serum electrolytes, and brain water content.
        Acta Neurochir Suppl. 2006; 96: 125-129
        • Donato T
        • Shapira Y
        • Artru A
        • Powers K.
        Effect of mannitol on cerebrospinal fluid dynamics and brain tissue edema.
        Anesth Analg. 1994; 78: 58-66
        • Sorani MD
        • Manley GT.
        Dose-response relationship of mannitol and intracranial pressure: a metaanalysis.
        J Neurosurg. 2008; 108: 80-87
        • Muizelaar JP
        • Lutz 3rd, HA
        • Becker DP.
        Effect of mannitol on ICP and CBF and correlation with pressure autoregulation in severely head-injured patients.
        J Neurosurg. 1984; 61: 700-706