Skip to main content
Log in

Treatment with Mannitol is Associated with Increased Risk for In-Hospital Mortality in Patients with Acute Ischemic Stroke and Cerebral Edema

  • Original Research Article
  • Published:
American Journal of Cardiovascular Drugs Aims and scope Submit manuscript

Abstract

Background

Current guidelines state that osmotic therapy is reasonable in patients with clinical deterioration from cerebral infarction-related cerebral edema. However, there are limited data on the safety and efficacy of this therapy. We aimed to evaluate the effect of mannitol on the outcome of ischemic stroke-related cerebral edema.

Methods and Results

We prospectively studied 922 consecutive patients admitted with acute ischemic stroke. Patients who showed space-occupying brain edema with tissue shifts compressing the midline structures received mannitol. The outcome was assessed with dependency rates at discharge (modified Rankin Scale grade 2–5) and in-hospital mortality. Rates of dependency were higher in patients treated with mannitol (n = 86) than in those who were not (97.7 and 58.5%, respectively; p < 0.001). Independent predictors of dependency were age, history of ischemic stroke and National Institutes of Health Stroke Scale (NIHSS) score at admission. Rates of mortality were higher in patients treated with mannitol than in those who were not (46.5 and 5.6%, respectively; p < 0.001). Independent predictors of in-hospital mortality were diastolic blood pressure [relative risk (RR) 1.05, 95% confidence interval (CI) 1.02–1.08, p < 0.001], NIHSS score at admission (RR 1.19, 95% CI 1.14–1.23, p < 0.001) and treatment with mannitol (RR 3.45, 95% CI 1.55–7.69, p < 0.005).

Conclusions

Administration of mannitol to patients with ischemic stroke-related cerebral edema does not appear to affect the functional outcome and might increase mortality, independently of stroke severity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. GBD 2015 Mortality and Causes of Death Collaborators. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388:1459–544.

    Article  Google Scholar 

  2. Murray CJ, Vos T, Lozano R, Naghavi M, Flaxman AD, Michaud C, Ezzati M, Shibuya K, Salomon JA, Abdalla S, Aboyans V, Abraham J, Ackerman I, Aggarwal R, Ahn SY, Ali MK, Alvarado M, Anderson HR, Anderson LM, Andrews KG, Atkinson C, Baddour LM, Bahalim AN, Barker-Collo S, Barrero LH, Bartels DH, Basáñez MG, Baxter A, Bell ML, Benjamin EJ, Bennett D, Bernabé E, Bhalla K, Bhandari B, Bikbov B, Bin Abdulhak A, Birbeck G, Black JA, Blencowe H, Blore JD, Blyth F, Bolliger I, Bonaventure A, Boufous S, Bourne R, Boussinesq M, Braithwaite T, Brayne C, Bridgett L, Brooker S, Brooks P, Brugha TS, Bryan-Hancock C, Bucello C, Buchbinder R, Buckle G, Budke CM, Burch M, Burney P, Burstein R, Calabria B, Campbell B, Canter CE, Carabin H, Carapetis J, Carmona L, Cella C, Charlson F, Chen H, Cheng AT, Chou D, Chugh SS, Coffeng LE, Colan SD, Colquhoun S, Colson KE, Condon J, Connor MD, Cooper LT, Corriere M, Cortinovis M, de Vaccaro KC, Couser W, Cowie BC, Criqui MH, Cross M, Dabhadkar KC, Dahiya M, Dahodwala N, Damsere-Derry J, Danaei G, Davis A, De Leo D, Degenhardt L, Dellavalle R, Delossantos A, Denenberg J, Derrett S, Des Jarlais DC, Dharmaratne SD, Dherani M, Diaz-Torne C, Dolk H, Dorsey ER, Driscoll T, Duber H, Ebel B, Edmond K, Elbaz A, Ali SE, Erskine H, Erwin PJ, Espindola P, Ewoigbokhan SE, Farzadfar F, Feigin V, Felson DT, Ferrari A, Ferri CP, Fèvre EM, Finucane MM, Flaxman S, Flood L, Foreman K, Forouzanfar MH, Fowkes FG, Fransen M, Freeman MK, Gabbe BJ, Gabriel SE, Gakidou E, Ganatra HA, Garcia B, Gaspari F, Gillum RF, Gmel G, Gonzalez-Medina D, Gosselin R, Grainger R, Grant B, Groeger J, Guillemin F, Gunnell D, Gupta R, Haagsma J, Hagan H, Halasa YA, Hall W, Haring D, Haro JM, Harrison JE, Havmoeller R, Hay RJ, Higashi H, Hill C, Hoen B, Hoffman H, Hotez PJ, Hoy D, Huang JJ, Ibeanusi SE, Jacobsen KH, James SL, Jarvis D, Jasrasaria R, Jayaraman S, Johns N, Jonas JB, Karthikeyan G, Kassebaum N, Kawakami N, Keren A, Khoo JP, King CH, Knowlton LM, Kobusingye O, Koranteng A, Krishnamurthi R, Laden F, Lalloo R, Laslett LL, Lathlean T, Leasher JL, Lee YY, Leigh J, Levinson D, Lim SS, Limb E, Lin JK, Lipnick M, Lipshultz SE, Liu W, Loane M, Ohno SL, Lyons R, Mabweijano J, MacIntyre MF, Malekzadeh R, Mallinger L, Manivannan S, Marcenes W, March L, Margolis DJ, Marks GB, Marks R, Matsumori A, Matzopoulos R, Mayosi BM, McAnulty JH, McDermott MM, McGill N, McGrath J, Medina-Mora ME, Meltzer M, Mensah GA, Merriman TR, Meyer AC, Miglioli V, Miller M, Miller TR, Mitchell PB, Mock C, Mocumbi AO, Moffitt TE, Mokdad AA, Monasta L, Montico M, Moradi-Lakeh M, Moran A, Morawska L, Mori R, Murdoch ME, Mwaniki MK, Naidoo K, Nair MN, Naldi L, Narayan KM, Nelson PK, Nelson RG, Nevitt MC, Newton CR, Nolte S, Norman P, Norman R, O’Donnell M, O’Hanlon S, Olives C, Omer SB, Ortblad K, Osborne R, Ozgediz D, Page A, Pahari B, Pandian JD, Rivero AP, Patten SB, Pearce N, Padilla RP, Perez-Ruiz F, Perico N, Pesudovs K, Phillips D, Phillips MR, Pierce K, Pion S, Polanczyk GV, Polinder S, Pope CA 3rd, Popova S, Porrini E, Pourmalek F, Prince M, Pullan RL, Ramaiah KD, Ranganathan D, Razavi H, Regan M, Rehm JT, Rein DB, Remuzzi G, Richardson K, Rivara FP, Roberts T, Robinson C, De Leòn FR, Ronfani L, Room R, Rosenfeld LC, Rushton L, Sacco RL, Saha S, Sampson U, Sanchez-Riera L, Sanman E, Schwebel DC, Scott JG, Segui-Gomez M, Shahraz S, Shepard DS, Shin H, Shivakoti R, Singh D, Singh GM, Singh JA, Singleton J, Sleet DA, Sliwa K, Smith E, Smith JL, Stapelberg NJ, Steer A, Steiner T, Stolk WA, Stovner LJ, Sudfeld C, Syed S, Tamburlini G, Tavakkoli M, Taylor HR, Taylor JA, Taylor WJ, Thomas B, Thomson WM, Thurston GD, Tleyjeh IM, Tonelli M, Towbin JA, Truelsen T, Tsilimbaris MK, Ubeda C, Undurraga EA, van der Werf MJ, van Os J, Vavilala MS, Venketasubramanian N, Wang M, Wang W, Watt K, Weatherall DJ, Weinstock MA, Weintraub R, Weisskopf MG, Weissman MM, White RA, Whiteford H, Wiebe N, Wiersma ST, Wilkinson JD, Williams HC, Williams SR, Witt E, Wolfe F, Woolf AD, Wulf S, Yeh PH, Zaidi AK, Zheng ZJ, Zonies D, Lopez AD, AlMazroa MA, Memish ZA. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380:2197–223.

    Article  PubMed  Google Scholar 

  3. Feigin VL, Forouzanfar MH, Krishnamurthi R, Mensah GA, Connor M, Bennett DA, Moran AE, Sacco RL, Anderson L, Truelsen T, O’Donnell M, Venketasubramanian N, Barker-Collo S, Lawes CM, Wang W, Shinohara Y, Witt E, Ezzati M, Naghavi M, Murray C, Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010) and the GBD Stroke Experts Group. Global and regional burden of stroke during 1990–2010: findings from the Global Burden of Disease Study 2010. Lancet. 2014;383:245–54.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Dostovic Z, Dostovic E, Smajlovic D, Ibrahimagic OC, Avdic L. Brain edema after ischaemic stroke. Med Arch. 2016;70:339–41.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Battey TW, Karki M, Singhal AB, Wu O, Sadaghiani S, Campbell BC, Davis SM, Donnan GA, Sheth KN, Kimberly WT. Brain edema predicts outcome after nonlacunar ischemic stroke. Stroke. 2014;45:3643–8.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Kasner SE, Demchuk AM, Berrouschot J, Schmutzhard E, Harms L, Verro P, Chalela JA, Abbur R, McGrade H, Christou I, Krieger DW. Predictors of fatal brain edema in massive hemispheric ischemic stroke. Stroke. 2001;32:2117–23.

    Article  PubMed  CAS  Google Scholar 

  7. Hacke W, Schwab S, Horn M, Spranger M, De Georgia M, von Kummer R. ‘Malignant’ middle cerebral artery territory infarction: clinical course and prognostic signs. Arch Neurol. 1996;53:309–15.

    Article  PubMed  CAS  Google Scholar 

  8. Qureshi AI, Suarez JI, Yahia AM, Mohammad Y, Uzun G, Suri MF, Zaidat OO, Ayata C, Ali Z, Wityk RJ. Timing of neurologic deterioration in massive middle cerebral artery infarction: a multicenter review. Crit Care Med. 2003;31:272–7.

    Article  PubMed  Google Scholar 

  9. Jüttler E, Unterberg A, Woitzik J, Bösel J, Amiri H, Sakowitz OW, Gondan M, Schiller P, Limprecht R, Luntz S, Schneider H, Pinzer T, Hobohm C, Meixensberger J. Hacke W; DESTINY II Investigators. Hemicraniectomy in older patients with extensive middle-cerebral-artery stroke. N Engl J Med. 2014;370:1091–100.

    Article  PubMed  CAS  Google Scholar 

  10. Vahedi K, Hofmeijer J, Juettler E, Vicaut E, George B, Algra A, Amelink GJ, Schmiedeck P, Schwab S, Rothwell PM, Bousser MG, van der Worp HB, Hacke W, DECIMAL, DESTINY, and HAMLET investigators. Early decompressive surgery in malignant infarction of the middle cerebral artery: a pooled analysis of three randomised controlled trials. Lancet Neurol. 2007;6:215–22.

    Article  PubMed  Google Scholar 

  11. Bardutzky J, Schwab S. Antiedema therapy in ischemic stroke. Stroke. 2007;38:3084–94.

    Article  PubMed  CAS  Google Scholar 

  12. Wijdicks EF, Sheth KN, Carter BS, Greer DM, Kasner SE, Kimberly WT, Schwab S, Smith EE, Tamargo RJ, Wintermark M, American Heart Association Stroke Council. Recommendations for the management of cerebral and cerebellar infarction with swelling: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45:1222–38.

    Article  PubMed  Google Scholar 

  13. Schwarz S, Georgiadis D, Aschoff A, Schwab S. Effects of body position on intracranial pressure and cerebral perfusion in patients with large hemispheric stroke. Stroke. 2002;33:497–501.

    Article  PubMed  Google Scholar 

  14. Christensen MS, Paulson OB, Olesen J, Alexander SC, Skinhoj E, Dam WH, Lassen NA. Cerebral apoplexy (stroke) treated with or without prolonged artificial hyperventilation. 1. Cerebral circulation, clinical course, and cause of death. Stroke. 1973;4:568–631.

    Article  PubMed  CAS  Google Scholar 

  15. Sandercock PA, Soane T. Corticosteroids for acute ischaemic stroke. Cochrane Database Syst Rev. 2011;9:CD000064.

    Google Scholar 

  16. Schwarz S, Georgiadis D, Aschoff A, Schwab S. Effects of hypertonic (10%) saline in patients with raised intracranial pressure after stroke. Stroke. 2002;33:136–40.

    Article  PubMed  CAS  Google Scholar 

  17. Diringer MN, Scalfani MT, Zazulia AR, Videen TO, Dhar R. Cerebral hemodynamic and metabolic effects of equi-osmolar doses mannitol and 23.4% saline in patients with edema following large ischemic stroke. Neurocrit Care. 2011;14:11–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Ong CJ, Keyrouz SG, Diringer MN. The role of osmotic therapy in hemispheric stroke. Neurocrit Care. 2015;23:285–91.

    Article  PubMed  CAS  Google Scholar 

  19. Koenig MA, Bryan M, Lewin JL 3rd, Mirski MA, Geocadin RG, Stevens RD. Reversal of transtentorial herniation with hypertonic saline. Neurology. 2008;70:1023–9.

    Article  PubMed  CAS  Google Scholar 

  20. Candelise L, Colombo A, Spinnler H. Therapy against brain swelling in stroke patients. A retrospective clinical study on 227 patients. Stroke. 1975;6:353–6.

    Article  PubMed  CAS  Google Scholar 

  21. 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;9:130–2.

    Article  PubMed  CAS  Google Scholar 

  22. Bereczki D, Mihálka L, Szatmári S, Fekete K, Di Cesar D, Fülesdi B, Csiba L, Fekete I. Mannitol use in acute stroke: case fatality at 30 days and 1 year. Stroke. 2003;34:1730–5.

    Article  PubMed  CAS  Google Scholar 

  23. Bereczki D, Fekete I, Prado GF, Liu M. Mannitol for acute stroke. Cochrane Database Syst Rev. 2007;3:CD001153.

    Google Scholar 

  24. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18:499–502.

    PubMed  CAS  Google Scholar 

  25. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, Coresh J, CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150:604–12.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Stokum JA, Gerzanich V, Simard JM. Molecular pathophysiology of cerebral edema. J Cereb Blood Flow Metab. 2016;36:513–38.

    Article  PubMed  CAS  Google Scholar 

  27. Steiner T, Pilz J, Schellinger P, Wirtz R, Friederichs V, Aschoff A, Hacke W. Multimodal online monitoring in middle cerebral artery territory stroke. Stroke. 2001;32:2500–6.

    Article  PubMed  CAS  Google Scholar 

  28. 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;29:1550–5.

    Article  PubMed  CAS  Google Scholar 

  29. Diringer MN, Zazulia AR. Osmotic therapy: fact and fiction. Neurocrit Care. 2004;1:219–33.

    Article  PubMed  CAS  Google Scholar 

  30. Videen TO, Zazulia AR, Manno EM, Derdeyn CP, Adams RE, Diringer MN, Powers WJ. Mannitol bolus preferentially shrinks non-infarcted brain in patients with ischemic stroke. Neurology. 2001;57:2120–2.

    Article  PubMed  CAS  Google Scholar 

  31. Manno EM, Adams RE, Derdeyn CP, Powers WJ, Diringer MN. The effects of mannitol on cerebral edema after large hemispheric cerebral infarct. Neurology. 1999;52:583–7.

    Article  PubMed  CAS  Google Scholar 

  32. Rosner MJ, Coley I. Cerebral perfusion pressure: a hemodynamic mechanism of mannitol and the postmannitol hemogram. Neurosurgery. 1987;21:147–56.

    Article  PubMed  CAS  Google Scholar 

  33. Famularo G. The puzzle of neuronal death and life: is mannitol the right drug for the treatment of brain oedema associated with ischaemic stroke? Eur J Emerg Med. 1999;6:363–8.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Konstantinos Tziomalos.

Ethics declarations

Funding

No external funding was used in the preparation of this manuscript.

Conflict of interest

MP, KT, SK, SMA, KC, SDB, MV, TD, CS and AIH declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Papagianni, M., Tziomalos, K., Kostaki, S. et al. Treatment with Mannitol is Associated with Increased Risk for In-Hospital Mortality in Patients with Acute Ischemic Stroke and Cerebral Edema. Am J Cardiovasc Drugs 18, 397–403 (2018). https://doi.org/10.1007/s40256-018-0285-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40256-018-0285-0

Navigation