This review examines the available data on the use of osmotic agents in patients with head injury and ischemic stroke, summarizes the physiological effects of osmotic agents, and presents the leading hypotheses regarding the mechanism by which they reduce ICP. Finally, it addresses the validity of the following commonly held beliefs: mannitol accumulates in injured brain; mannitol shrinks only normal brain and can increase midline shift; osmolality can be used to monitor mannitol administration; mannitol should be not be administered if osmolality is > 320 mOsm; and hypertonic saline is equally effective as mannitol.
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Kaufmann AM, Cardoso ER. Aggravation of vasogenic cerebral edema by multiple-dose mannitol. J Neurosurg 1992;77:584–589.
Frank JI. Large hemispheric infarction, deterioration, and intracranial pressure. Neurology 1995;45:1286–1290.
Berger S, Schurer L, Hartl R, Messmer K, Baethmann A. Reduction of post-traumatic intracranial hypertension by hypertonic/hyperoncotic saline/dextran and hypertonic mannitol. Neurosurgery 1995;37:98–107.
Gemma M, Cozzi S, Tommasino C, Mungo M, Calvi MR, Cipriani A, et al. 7.5% hypertonic saline versus 20% mannitol during elective neurosurgical supratentorial procedures. J Neurosurg Anesthesiol 1997;9:329–334.
Horn P, Munch E, Vajkoczy P, Herrmann P, Quintel M, Schilling L, et al. Hypertonic saline solution for control of elevated intracranial pressure in patients with exhausted response to mannitol and barbiturates. Neurol Res 1999;21:758–764.
Khanna S, Davis D, Peterson B, Fisher B, Tung H, O’Quigley J, et al. Use of hypertonic saline in the treatment of severe refractory posttraumatic intracranial hypertension in pediatric traumatic brain injury. Crit Care Med 2000;28:1144–1151.
Alvarez B, Ferrer-Sueta G, Radi R. Slowing of peroxynitrite decomposition in the presence of mannitol and ethanol. Free Radic Biol Med 1998;24:1331–1337.
Korenkov AI, Pahnke J, Frei K, Warzok R, Schroeder HW, Frick R, et al. Treatment with nimodipine or mannitol reduces programmed cell death and infarct size following focal cerebral ischemia. Neurosurg Rev 2000;23:145–150.
Weed LH, McKibbens PR. Experimental alterations of brain bulk. Am J Physiol 1919;48:512–530.
Wise BL, Chater N. The value of hypertonic mannitol solution in decreasing brain mass and lowering cerebrospinal fluid pressure. J Neurosurg 2002;19:1038–1043.
Olson JE, Banks M, Dimlich RV, Evers J. Blood-brain barrier water permeability and brain osmolyte content during edema development. Acad Emerg Med 1997;4:662–673.
Rosenberg GA, Kyner WT, Fenstermacher JD, Patlak CS. Effect of vasopressin on ependymal and capillary permeability to tritiated water in cat. Am J Physiol 1986;251:F485-F489.
Fenstermacher JD. Volume regulation of the CNS. In: Edema. (Straub NC, Taylor AE, ed.). Raven Press, New York, 1984.
Amtorp O. Estimation of capillary permeability of inulin, sucrose and mannitol in rat brain cortex. Acta Physiol Scand 1980;110:337–342.
Matsuoka Y, Hossmann K. Brain tissue osmolality after middle cerebral artery occlusion in cats. Exp Neurol 1982;77:599–611.
Bowers SA, Marshall LF. Outcome in 200 consecutive cases of severe head injury treated in San Diego County: a prospective analysis. Neurosurgery 1980;6:237–242.
Adrogue HJ, Madias, NE. Hypernatremia. N Engl J Med 2000;342:1493–1499.
Gullans, SR. and Verbalis JG. Control of brain volume during hyperosmolar and hypoosmolar conditions. Annu Rev Med 1993;44:289–301.:289–301.
McManus ML, Churchwell KB, Strange K. Regulation of cell volume in health and disease. N Engl J Med 1995;333:1260–1266.
McDowell ME, Wolf AV, Steer A. Osmotic volumes of distribution. Idiogenic changes in osmotic pressure associated with administration of hypertonic solutions. Am J Physiol 1955;180:545–558.
Go KG. The fluid environment of the central nervous system. In: Cerebral pathophysiology. (Go KG, ed.). Elsevier, New York, 1991.
Wallasch TM. [The value of transcranial Doppler sonography in neurosurgery]. Neurochirurgia 1990;33(Suppl 1):58–60.
Javid M, Anderson J. The effect of urea on cerebrospinal fluid pressure in monkeys before and after bilateral nephrectomy. J Lab Clin Med 1959;53:484–489.
Willerson JT, Curry GC, Atkins JM, Parkey R, Horwitz LD. Influence of hypertonic mannitol on ventricular performance and coronary blood flow in patients. Circulation 1975;51:1095–1100.
Shackford SR, Bourguignon PR, Wald SL, Rogers FB, Osler TM, Clark DE. Hypertonic saline resuscitation of patients with head injury: a prospective, randomized clinical trial. J Trauma 1998;44:50–58.
Burke AM, Quest DO, Chien S, Cerri C. The effects of mannitol on blood viscosity. J Neurosurg 1981;55:550–553.
Hijiya N, Horiuchi K, Asakura T. Morphology of sickle cells produced in solutions of varying osmolarities. J Lab Clin Med 1991;117:60–66.
Kiesewetter H, Dauer U, Teitel P, Schmid-Schonbein H, Trapp R. The single erythrocyte rigidometer (SER) as a reference for RBC deformability. Biorheology 1982;19:737–753.
Cloyd JC, Snyder BD, Cleermans B, et al. Mannitol pharmacokinetics and serum osmolality in dogs and humans. J Pharmacol Exp Ther 1986;236:301–306.
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.
Domingues R, Corcoran AC, Page IH. Mannitol: kinetics of distribution, excretion, and utilization in human beings. J Lab Clin Med 1947;32:1192–1202.
Wise BL, Perkins RK, Stevenson E, Scott GS. Penetration of C14-labelled mannitol from serum into cererbrospinal fluid and brain. Exp Neurol 2002;10:264–270.
Nau R, Desel H, Lassek C, Thiel A, Schinschke S, Rossing R, et al. Slow elimination of mannitol from human cerebrospinal fluid. Eur J Clin Pharmacol 1997;53:271–274.
Anderson P, Boreus L, Gordon E, Lagerkranser M, Rudehill A, Lindquist C, et al. Use of mannitol during neurosurgery: Interpatient variability in the plasma and CSF levels. Eur J Clin Pharmacol 1988;35:643–649.
James HE. Methodology for the control of intracranial pressure with hypertonic mannitol. Acta Neurochir (Wien) 1980;51:161–172.
McGraw CP, Alexander E Jr, Howard G. Effect of dose and dose schedule on the response of intracranial pressure to mannitol. Surg Neurol 1978;10:127–130.
Roberts PA, Pollay M, Engles C, Pendleton B, Reynolds E, Stevens, FA. Effect on intracranial pressure of furosemide combined with varying doses and administration rates of mannitol. J Neurosurg 1987;66:440–446.
Marshall LF, Smith RW, Rauscher A, Shapiro HM. Mannitol dose requirements in brain-injured patients. J Neurosurg 1978;48:169–172.
McGraw CP, Howard G. Effect of mannitol on increased intracranial pressure. Neurosurgery 1983; 13(3):269–271.
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.
Albright AL, Latchaw RE. Effects of osmotic and oncodiuretic therapy on CT-brain density and intracranial pressure. Acta Neurochir. (Wien) 1985; 78:119–122.
Hartwell RC, Sutton LN. Mannitol, intracranial pressure, and vasogenic edema. Neurosurgery 1993;32:444–450.
Albright AL, Latchaw RE, Robinson AG. Intracranial and systemic effects of osmotic and oncotic therapy in experimental cerebral edema. J Neurosurg 1984;60:481–489.
Paczynski RP, He YY, Diringer MN, Hsu CY. Multiple-dose mannitol reduces brain water content in a rat model of cortical infarction. Stroke 1997;28:1437–1443.
Paczynski RP, Venkatesan R, Diringer MN, He YY, Hsu CY, Lin WL. Effects of fluid management on edema volume and midline shift in a rat model of ischemic stroke. Stroke 2000;31:1702–1708.
Nath F, Galbraith S. The effect of mannitol on cerebral white matter water content. J Neurosurg 1986;65:41–43.
Cascino T, Baglivo J, Conti J, Szewczykowski J, Posner JB, Rottenberg DA. Quantitative CT assessment of furosemide- and mannitol-induced changes in brain water content. Neurology 1983;33:898–903.
Videen TO, Zazulia AR, Manno EM, Derdeyn CP, Adams RE, Diringer MN, et al. Mannitol bolus preferentially shrinks non-infarcted brain in patients with ischemic stroke. Neurology 2001;57:2120–2122.
Freshman SP, Battistella FD, Matteucci M, Wisner DH. Hypertonic saline (7.5%) versus mannitol: A comparison for treatment of acute head injuries. J Trauma 1993;35:344–348.
Berger S, Schurer L, Hartl R, Deisbock T, Dautermann C, Murr R, et al. 7.2% NaCl/10% dextran 60 versus 20% mannitol for treatment of intracranial hypertension. Acta Neurochir Suppl (Wien) 1994;60:494–498.
Wisner DH, Schuster L, Quinn C. Hypertonic saline resuscitation of head injury: Effects on cerebral water content. J Trauma 1990;30:75–78.
Rosner MJ. Introduction to cerebral perfusion pressure management. Neurosurg Clin N Am 1995;6:761–773.
Rosner MJ, Rosner SD, Johnson AH. Cerebral perfusion pressure: management protocol and clinical results. J Neurosurg 1995;83:949–962.
Rosner MJ, Coley I. Cerebral perfusion pressure: a hemodynamic mechanism of mannitol and the postmannitol hemogram. Neurosurgery 1987;21:147–156.
Bouma GJ, Muizelaar JP, Bandoh K, Marmarou A. Blood pressure and intracranial pressure-volume dynamics in severe head injury: Relationship with cerebral blood flow. Journal of Neurosurgery 1992;77:15–19.
Cold GE. Cerebral blood flow in acute head injury. The regulation of cerebral blood flow and metabolism during the acute phase of head injury, and its significance for therapy. Acta Neurochir Suppl 1990;49:1–64.
Dernbach PD, Little JR, Jones SC, Ebrahim ZY. Altered cerebral autoregulation and CO2 reactivity after aneurysmal subarachnoid hemorrhage. Neurosurgery 1988;22:822–826.
Enevoldsen EM, Jensen FT. Autoregulation and CO2 responses of cerebral blood flow in patients with acute severe head injury. J Neurosurg 1978;48:689–703.
Hashi K, Meyer JS, Shinmaru S, Welch KMA, Teraura, T. Changes in vasomotor reactivity to CO2 and autoregulation following experimental subarachnoid hemorrhage. J Neurol Sci 1972;17:15–22.
Muizelaar JP, van der Poel HG, Li ZC, Kontos HA, Levasseur JE. Pial arteriolar vessel diameter and CO2 reactivity during prolonged hyperventilation in the rabbit. J Neurosurg 1988;69:923–927.
Auer LM, Haselberber K. Effect of intravenous mannitol on cat pial arteries and veins during normal and elevated intracranial pressure. Neurosurgery 1987;21:142–146.
Lin W, Paczynski RP, Kuppusamy K, Hsu CY, Haacke EM. Quantitative measurements of regional cerebral blood volume using MRI in rats: Effects of arterial carbon dioxide tension and mannitol. Magn Reson Med 1997;38:420–428.
Ravussin P, Archer DP, Meyer E, Abou-Madi M, Yamamoto L, Trop D. The effects of rapid infusions of saline and mannitol on cerebral blood volume and intracranial pressure in dogs. Can Anaesth Soc J 1985;32:506–515.
Inao S, Kuchiwaki H, Wachi A, Andoh K, Nagasaka M, Sugita K, et al. Effect of mannitol on intracranial pressure-volume status and cerebral haemodynamics in brain oedema. Acta Neurochir Suppl (Wien) 1990;51:401–403.
Ravussin P, Archer DP, Tyler JL, Meyer E, Abou Madi M, Diksic M, et al. Effects of rapid mannitol infusion on cerebral blood volume. A positron emission tomographic study in dogs and man. J Neurosurg 1986;64:104–113.
Chi OZ, Wei HM, Lu X, Weiss HR. Increased blood-brain permeability with hyperosmolar mannitol increases cerebral O2 consumption and O2 supply/consumption heterogeneity. J Cereb Blood Flow Metab 1996;16:327–333.
Brown FD, Johns L, Jafar JJ, Crockard HA, Mullan S. Detailed monitoring of the effects of mannitol following experimental head injury. J Neurosurg 1979;50:423–432.
Hartl R, Bardt TF, Kiening KL, Sarrafzadeh AS, Schneider GH, Unterberg AW. Mannitol decreases ICP but does not improve brain-tissue pO2 in severely head-injured patients with intracranial hypertension. Acta Neurochir Suppl (Wien) 1997;70:40–42.
Allen CH, Ward JD. An evidence-based approach to management of increased intracranial pressure. Crit Care Clin 1998;14:485–495.
Bullock R. Mannitol and other diuretics in severe neurotrauma. New Horizon 1995;3:448–452.
Roberts I, Schierhout G, Wakai A. Mannitol for acute traumaticbrain injury (Cochrane Review). Cochrane Database Syst Rev 2003;2:CD001049.
Smith HP, Kelly DLJ, McWhorter JM, Armstrong D, Johnson R, Transou C, et al. Comparison of mannitol regimens in patients with severe head injury undergoing intracranial monitoring. J Neurosurg 1986;65:820–824.
Peterson B, Khanna S, Fisher B, Marshall L. Prolonged hypernatremia controls elevated intracranial pressure in head-injured pediatric patients. Crit Care Med 2000;28:1136–1143.
Qureshi AI, Suarez JI, Castro A, Bhardwaj A. Use of hypertonic saline/acetate infusion in treatment of cerebral edema in patients with head trauma: Experience at a single center. J Trauma 1999;47:659–665.
Munar F, Ferrer AM, de Nadal M, Poca MA, Pedraza S, Sahuquillo J, et al. Cerebral hemodynamic effects of 7.2% hypertonic saline in patients with head injury and raised intracranial pressure. J Neurotrauma 2000;17:41–51.
Zornow MH. Hypertonic saline as a safe and efficacious treatment of intracranial hypertension. J Neurosurg Anesthesiol 1996;8:175–177.
Battistella FD, Wisner DH. Combined hemorrhagic shock and head injury: Effects of hypertonic saline (7.5%) resuscitation. J Trauma 1991;31:182–188.
Silver FL, Norris JW, Lewis AJ, Hachinski VC. Early mortality following stroke: A prospective review. Stroke 1984;15:492–496.
Longstreth WT Jr, Bernick C, Fitzpatrick A, Cushman M, Knepper L, Lima J, et al. Frequency and predictors of stroke death in 5,888 participants in the Cardiovascular Health Study. Neurology 2001;56:368–375.
Johnston KC, Li JY, Lyden PD, Hanson SK, Feasby TE, Adams RJ, et al. Medical and neurological complications of ischemic stroke: Experience from the RANTTAS trial. RANTTAS Investigators. Stroke 1998;29:447–453.
Davalos A, Toni D, Iweins F, Lesaffre E, Bastianello S, Castillo J. Neurological deterioration in acute ischemic stroke: Potential predictors and associated factors in the European cooperative acute stroke study (ECASS) I. Stroke 1999;30:2631–2636.
Wing SD, Norman D, Pollock JA, Newton TH. Contrast enhancement of cerebral infarcts in computed tomography. Radiology 1976;121:89–92.
Inoue Y, Takemoto K, Miyamoto T, Yoshikawa N, Taniguchi S, Saiwai S, et al. Sequential computed tomography scans in acute cerebral infarction. Radiology 1980;135:655–662.
Yoc, DH Jr, Marshall WH Jr. Recent ischemic brain infarcts at computed tomography: appearances pre- and postcontrast infusion. Radiology 1975;117:599–608.
Schwab S, Steiner T, Aschoff A, Schwarz S, Steiner HH, Jansen O, et al. Early hemicraniectomy in patients with complete middle cerebral artery infarction. Stroke 1998;29:1888–1893.
Delashaw JB, Broaddus WC, Kassell NF, Haley EC, Pendleton GA, Vollmer DG, et al. Treatment of right hemisphere cerebral infarction by hemicraniectomy. Stroke 1990;21:874–881.
Wijdicks EF. Management of massive hemispheric cerebral infarct: Is there a ray of hope? Mayo Clin Proc 2000;75:945–952.
Marion DW, Obrist WD, Carlier PM, Penrod LE, Darby JM. The use of moderate therapeutic hypothermia for patients with severe head injuries: A preliminary report. J Neurosurg 1993;79:354–362.
Karibe H, Zarow GJ, Weinstein PR. Use of mild intraischemic hypothermia versus mannitol to reduce infarct size after temporary middle cerebral artery occlusion in rats. J Neurosurg 1995;83:93–98.
Pena H, Gaines C, Suess D, Crowell RM, Waggener JD, DeGirolami U. Effect of mannitol on experimental focal ischemia in awake monkeys. Neurosurgery 1982;11:477–481.
Kobayashi H, Ide H, Kodera T, Handa Y, Kabuto M, Kubota T, et al. Effect of mannitol on focal cerebral ischemia evaluated by magnetic resonance imaging. Acta Neurochir Suppl (Wien) 1994;60:228–230.
Luvisotto TL, Auer RN, Sutherland GR. The effect of mannitol on experimental cerebral ischemia, revisited. Neurosurgery 1996;38:131–138.
Suzuki J, Tanaka S, Yoshimoto T. Recirculation in the acute period of cerebral infarction: Brain swelling and its suppression using mannitol. Surg Neurol 1980;14:467–472.
Candelise L, Colombo A, Spinnler H. Therapy against brain swelling in stroke patients. A retrospective clinical study on 227 patients. Stroke 1975;6:353–356.
Santambrogio S, Martinotti R, Sardella F, Porro F, Randazzo, A. Is there a real treatment for stroke? Clinical and statistical comparison of different treatments in 300 patients. Stroke 1978;9:130–132.
Schwarz S, Schwab S, Bertram M, Aschoff A, Hacke, W. Effects of hypertonic saline hydroxyethyl starch solution and mannitol in patients with increased intracranial pressure after stroke. Stroke 1998;29:1550–1555.
Bereczki D, Mihalka L, Szatmari S, Fekete K, Di Cesar D, Fulesdi B, et al. Mannitol use in acute stroke: case fatality at 30 days and 1 year. Stroke 2003;34:1730–1735.
Adams HP Jr, Brott TG, Crowell RM, Furlan AJ, Gomez CR, Grotta J, et al. Guidelines for the management of patients with acute ischemic stroke. A statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke 1994;25:1901–1914.
Toung TJ, Hurn PD, Traystman RJ, Bhardwaj A. Global brain water increases after experimental focal cerebral ischemia: effect of hypertonic saline. Crit Care Med 2002;30:644–649.
Bhardwaj A, Harukuni I, Murphy SJ, Alkayed NJ, Crain BJ, Koehler RC, et al. Hypertonic saline worsens infarct volume after transient focal ischemia in rats. Stroke 2000;31:1694–1701.
Schwarz S, Georgiadis D, Aschoff A, Schwab S. Effects of hypertonic (10%) saline in patients with raised intracranial pressure after stroke. Stroke 2002;33:136–140.
Suarez JI, Qureshi AI, Bhardwaj A, Williams MA, Schnitzer MS, Mirski M, et al. Treatment of refractory intracranial hypertension with 23.4% saline. Crit Care Med 1998;26:1118–1122.
Suzuki J, Fujimoto S, Mizoi K, Oba, MThe protective effect of combined administration of antioxidants and perfluorochemicals on cerebral ischemia. Stroke 1984;15:672–679.
Steiner T, Weber R, Krieger D. Increased intracerebral pressure following stroke. Curr. Treatment Options Neurol 2001;3:441–450.
Schwab S, Aschoff A, Spranger M, Albert F, Hacke W. The value of intracranial pressure monitoring in acute hemispheric stroke. Neurology 1996;47:393–398.
Fishman RA. Brain edema. N Engl J Med 1975;293:706–711.
Maioriello AV, Chaljub G, Nauta, HJ, Lacroix M. Chemical shift imaging of mannitol in acute cerebral ischemia. Case report. J Neurosurg 2002;97:687–691.
McManus ML, Soriano, SG. Rebound swelling of astroglial cells exposed to hypertonic mannitol. Anesthesiology 1998;88:1586–1591.
Manno EM, Adams RE, Derdeyn CP, Powers WJ, Diringer MN. The effects of mannitol on cerebral edema after large hemispheric cerebral infarct. Neurology 1999;52:583–587.
García-Morales EJ, Cariappa A, Parvin CA, Scott MG, Diringer MN. Use of the osmole gap to monitor serum mannitol levels. Neurology 2003;60:A364.
The Brain Trauma Foundation. The American Association of Neurological Surgeons. The Joint Section on Neurotrauma and Critical Care. Guidelines for cerebral perfusion pressure. J Neurotrauma 2000;17:507–511.
Becker, DP, Vries J. The alleviation of increased intracranial pressure by the chronic administration of osmotic agents. In: Intracranial pressure (Brock M, Dietz H, ed.). Springer, New York, 1972.
Feig PU, McCurdy DK. The hypertonic state. N Engl J Med 1977;197:1444–1454.
Aiyagari, Diringer MN. Hypernatremia and mortality in the neurology/neurosurgery intensive care unit. Neurology 2001;56:A469.
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Diringer, M.N., Zazulia, A.R. Osmotic therapy. Neurocrit Care 1, 219–233 (2004). https://doi.org/10.1385/NCC:1:2:219
- hypertonic saline
- head injury
- ischemic stroke
- intracranial pressure