Neurocritical Care

, Volume 8, Issue 1, pp 13–18

An Association of Prior Statin Use with Decreased Perihematomal Edema

  • Neeraj S. Naval
  • Tamer A. Abdelhak
  • Nathalie Urrunaga
  • Paloma Zeballos
  • Marek A. Mirski
  • Juan R. Carhuapoma
Original Paper



To investigate the impact of statins on perihematomal edema following spontaneous supratentorial intracerebral hemorrhage (ICH).


Hematoma expansion and evolution of perihematomal edema are most commonly responsible for neurological deterioration following ICH. A possible role of statins in reducing perihematomal edema has been suggested based on studies in animal models.


Records of consecutive ICH patients admitted to The Johns Hopkins Hospital from 1999 to 2006 were reviewed. Patients with ICH related to trauma or underlying lesions (e.g., brain tumors, aneurysms, and arterio-venous malformations) and of infratentorial location were excluded. Absolute and relative perihematomal edema were assessed on initial head CT. Using regression analysis, the impact of prior statin use on absolute and relative edema at presentation was assessed correcting for other factors possibly impacting perihematomal edema, such as age, coagulopathy, aspirin use, admission mean arterial pressure (MAP), and blood glucose.


A total of 125 consecutive ICH patients were studied. Patients with prior statin exposure had a mean edema volume of 13.2 ± 9.2 cc compared to 22.3 ± 18.3 cc in patients who were not using statins at the time of ICH. Following multiple linear regression analysis, we have identified a statistically significant association between prior statin use with reduced early absolute perihematomal edema (P = 0.035). Mean relative perihematomal edema was significantly lower in patients on statins at presentation (0.44) as opposed to 0.81 in patients with no prior statin use. This difference remained statistically significant (P = 0.021) after correcting for other variables.


We report the association between statin use prior to ICH and decreased absolute and relative perihematomal edema. A prospective study analyzing the role of statins in perihematomal edema reduction and the resultant effect on mortality and functional outcomes following ICH is warranted.


Intracerebral hemorrhage Edema Statins 


  1. 1.
    Broderick JP, Brott T, Tomsick T, Miller R, Huster G. Intracerebral hemorrhage more than twice as common as subarachnoid hemorrhage. J Neurosurg 1993 78(2):188–91.PubMedGoogle Scholar
  2. 2.
    Qureshi AI, Tuhrim S, Broderick JP, Batjer HH, Hondo H, Hanley DF. Spontaneous intracerebral hemorrhage. N Engl J Med 2001;344:1450–60.PubMedCrossRefGoogle Scholar
  3. 3.
    Mayer SA, Sacco RL, Shi T, Mohr JP. Neurologic deterioration in noncomatose patients with supratentorial intracerebral hemorrhage. Neurology 1994 44(8):1379–84.PubMedGoogle Scholar
  4. 4.
    Mayer SA, Brun NC, Begtrup K, Broderick J, Davis S, Diringer MN, Skolnick BE, Steiner T. Recombinant Activated Factor VII Intracerebral Hemorrhage Trial Investigators. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2005;352(8):777–85.PubMedCrossRefGoogle Scholar
  5. 5.
    Gong Y, Hua Y, Keep RF, Hoff JT, Xi G. Intracerebral hemorrhage: effects of aging on brain edema and neurological deficits. Stroke 2004;35(11):2571–5.PubMedCrossRefGoogle Scholar
  6. 6.
    Gebel JM, Brott TG, Sila CA, Tomsick TA, Jauch E, Salisbury S, Khoury J, Miller R, Pancioli A, Duldner JE, Topol EJ, Broderick JP. Decreased perihematomal edema in thrombolysis-related intracerebral hemorrhage compared with spontaneous intracerebral hemorrhage. Stroke 2000;31(3):596–600.PubMedGoogle Scholar
  7. 7.
    Wagner KR, Xi G, Hua Y, de Courten-Meyers G, Broderick JP, Brott TG. Ultra-early clot aspiration after lysis with tissue plasminogen activator in a porcine model of intracerebral hemorrhage: edema reduction and blood brain barrier protection. J Neurosurg 1999;90:491–8.PubMedGoogle Scholar
  8. 8.
    Sansing LH, Kaznatcheeva EA, Perkins CJ, Komaroff E, Gutman FB, Newman GC. Edema after intracerebral hemorrhage: correlations with coagulation parameters and treatment. J Neurosurg 2003;98(5):985–92.PubMedGoogle Scholar
  9. 9.
    Song EC, Chu K, Jeong SW, Jung KH, Kim SH, Kim M, Yoon BW. Hyperglycemia exacerbates brain edema and perihematomal cell death after intracerebral hemorrhage. Stroke 2003;34(9):2215–20.PubMedCrossRefGoogle Scholar
  10. 10.
    Gong C, Boulis N, Qian J, Turner DE, Hoff JT, Keep RF. Intracerebral hemorrhage-induced neuronal death. Neurosurgery 2001;48(4):875–82; discussion 882–3.PubMedCrossRefGoogle Scholar
  11. 11.
    Wagner KR, Xi G, Hua Y, Kleinholz M, de Courten-Myers GM, Myers RE, Broderick JP, Brott TG. Lobar intracerebral hemorrhage model in pigs: rapid edema development in perihematomal white matter. Stroke 1996;27:490–7.PubMedGoogle Scholar
  12. 12.
    Lee KR, Betz AL, Kim S, Keep RF, Hoff JT. The role of the coagulation cascade in brain edema formation after intracerebral hemorrhage. Acta Neurochir (Wien) 1996;138:396–401.CrossRefGoogle Scholar
  13. 13.
    Lee KR, Colon GP, Betz AL, Keep RF, Kim S, Hoff JT. Edema from intracerebral hemorrhage: the role of thrombin. J Neurosurg 1996;84:91–6.PubMedGoogle Scholar
  14. 14.
    Lee KR, Kawai N, Kim S, Sagher O, Hoff JT. Mechanisms of edema formation after intracerebral hemorrhage: effects of thrombin on cerebral blood flow, blood–brain barrier permeability, and cell survival in a rat model. J Neurosurg 1997;86:272–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Xi G, Wagner KR, Keep RF, Hua Y, de Courten-Myers GM, Broderick JP, Brott TG, Hoff JT, Muizelaar JP. Role of blood clot formation on early edema development after experimental intracerebral hemorrhage. Stroke 1998;29:2580–6.PubMedGoogle Scholar
  16. 16.
    Lee KR, Betz AL, Keep RF, Chenevert TL, Kim S, Hoff JT. Intracerebral infusion of thrombin as a cause of brain edema. J Neurosurg 1995;83:1045–50.PubMedGoogle Scholar
  17. 17.
    Lee KR, Drury I, Vitarbo E, Hoff JT. Seizures induced by intracerebral injection of thrombin: a model of intracerebral hemorrhage. J Neurosurg 1997;87:73–8.PubMedGoogle Scholar
  18. 18.
    Xi G, Hua Y, Keep RF, Younger JG, Hoff JT. Systemic complement depletion diminishes perihematomal brain edema in rats. Stroke 2001;32:162–7.PubMedCrossRefGoogle Scholar
  19. 19.
    Butcher KS, Baird T, MacGregor L, Desmond P, Tress B, Davis S. Perihematomal edema in primary intracerebral hemorrhage is plasma derived. Stroke 2004;35(8):1879–85.PubMedCrossRefGoogle Scholar
  20. 20.
    Fainardi E, Borrelli M, Saletti A, Schivalocchi R, Russo M, Azzini C, Cavallo M, Ceruti S, Tamarozzi R, Chieregato A. Evaluation of acute perihematomal regional apparent diffusion coefficient abnormalities by diffusion-weighted imaging. Acta Neurochir Suppl 2006;96:81–4.PubMedCrossRefGoogle Scholar
  21. 21.
    Ardizzone TD, Lu A, Wagner KR, Tang Y, Ran R, Sharp FR. Glutamate receptor blockade attenuates glucose hypermetabolism in perihematomal brain after experimental intracerebral hemorrhage in rat. Stroke 2004;35(11):2587–91.PubMedCrossRefGoogle Scholar
  22. 22.
    Sinn DI, Lee ST, Chu K, Jung KH, Kim EH, Kim JM, Park DK, Song EC, Kim BS, Yoon SS, Kim M, Roh JK. Proteasomal inhibition in intracerebral hemorrhage: neuroprotective and anti-inflammatory effects of bortezomib. Neurosci Res 2007;58(1):12–8.PubMedCrossRefGoogle Scholar
  23. 23.
    Lee ST, Chu K, Sinn DI, Jung KH, Kim EH, Kim SJ, Kim JM, Ko SY, Kim M, Roh JK. Erythropoietin reduces perihematomal inflammation and cell death with eNOS and STAT3 activations in experimental intracerebral hemorrhage. J Neurochem 2006;96(6):1728–39.PubMedCrossRefGoogle Scholar
  24. 24.
    Chu K, Jeong SW, Jung KH, Han SY, Lee ST, Kim M, Roh JK. Celecoxib induces functional recovery after intracerebral hemorrhage with reduction of brain edema and perihematomal cell death. J Cereb Blood Flow Metab 2004;24(8):926–33.PubMedCrossRefGoogle Scholar
  25. 25.
    Sinn DI, Lee ST, Chu K, Jung KH, Song EC, Kim JM, Park DK, Kim M, Roh JK. Combined neuroprotective effects of celecoxib and memantine in experimental intracerebral hemorrhage. Neurosci Lett 2007;411(3):238–42.PubMedCrossRefGoogle Scholar
  26. 26.
    Vaughan CJ, Murphy MB, Buckley BM. Statins do more than just lower cholesterol. Lancet 1996;348(9034):1079–82. (Erratum in Lancet 1997 Jan 18;349(9046):214.).PubMedCrossRefGoogle Scholar
  27. 27.
    Laufs U, La Fata V, Plutzky J, Liao JK. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 1998;97:1129–35.PubMedGoogle Scholar
  28. 28.
    McGirt MJ, Lynch JR, Parra A, Sheng H, Pearlstein RD, Laskowitz DT, Pelligrino DA, Warner DS. Simvastatin increases endothelial nitric oxide synthase and ameliorates cerebral vasospasm resulting from subarachnoid hemorrhage. Stroke 2002;33(12):2950–6.PubMedCrossRefGoogle Scholar
  29. 29.
    Laufs U, Gertz K, Huang P, Nickenig G, Bohm M, Dirnagl U, Endres M. Atorvastatin upregulates type III nitric oxide synthase in thrombocytes, decreases platelet activation, and protects from cerebral ischemia in normocholesterolemic mice. Stroke 2000;31(10):2442–9.PubMedGoogle Scholar
  30. 30.
    Kawashima S, Yamashita T, Miwa Y, Ozaki M, Namiki M, Hirase T, Inoue N, Hirata K, Yokoyama M. HMG-CoA reductase inhibitor has protective effects against stroke events in stroke-prone spontaneously hypertensive rats. Stroke 2003;34:157–63.PubMedCrossRefGoogle Scholar
  31. 31.
    Amin-Hanjani S, Stagliano NE, Yamada M, Huang PL, Liao JK, Moskowitz MA. Mevastatin, an HMG-CoA reductase inhibitor, reduces stroke damage and upregulates endothelial nitric oxide synthase in mice. Stroke 2001;32:980–6.PubMedGoogle Scholar
  32. 32.
    Vaughan CJ, Delanty N. Neuroprotective properties of statins in cerebral ischemia and stroke. Stroke 1999;30:1969–73.PubMedGoogle Scholar
  33. 33.
    Chen J, Zhang ZG, Li Y, Wang Y, Wang L, Jiang H, Zhang C, Lu M, Katakowski M, Feldkamp CS, Chopp M. Statins induce angiogenesis, neurogenesis, and synaptogenesis after stroke. Ann Neurol 2003;53:743–51.PubMedCrossRefGoogle Scholar
  34. 34.
    Kuhlmann CR, Lessmann V, Luhmann HJ. Fluvastatin stabilizes the blood–brain barrier in vitro by nitric oxide-dependent dephosphorylation of myosin light chains. Neuropharmacology 2006;51:907–13.PubMedCrossRefGoogle Scholar
  35. 35.
    Nagaraja TN, Knight RA, Croxen RL, Konda KP, Fenstermacher JD. Acute neurovascular unit protection by simvastatin in transient cerebral ischemia. Neurol Res 2006;28:826–30.PubMedCrossRefGoogle Scholar
  36. 36.
    Stueve O. Statins and the blood–brain barrier: plugging the holes. Ann Neurol 2006;60:1–2.CrossRefGoogle Scholar
  37. 37.
    Jung KH, Chu K, Jeong SW, Han SY, Lee ST, Kim JY, Kim M, Roh JK. HMG-CoA reductase inhibitor, atorvastatin, promotes sensorimotor recovery, suppressing acute inflammatory reaction after experimental intracerebral hemorrhage. Stroke 2004;35(7):1744–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Seyfried D, Han Y, Lu D, Chen J, Bydon A, Chopp M. Improvement in neurological outcome after administration of atorvastatin following experimental intracerebral hemorrhage in rats. J Neurosurg 2004;101(1):104–7.PubMedGoogle Scholar
  39. 39.
    Gebel JM Jr, Jauch EC, Brott TG, Khoury J, Sauerbeck L, Salisbury S, Spilker J, Tomsick TA, Duldner J, Broderick JP. Natural history of perihematomal edema in patients with hyperacute spontaneous intracerebral hemorrhage. Stroke 2002;33(11):2631–5.PubMedCrossRefGoogle Scholar
  40. 40.
    Gebel JM Jr, Jauch EC, Brott TG, Khoury J, Sauerbeck L, Salisbury S, Spilker J, Tomsick TA, Duldner J, Broderick JP. Relative edema volume is a predictor of outcome in patients with hyperacute spontaneous intracerebral hemorrhage. Stroke 2002;33(11):2636–41.PubMedCrossRefGoogle Scholar
  41. 41.
    Naff NJ, Carhuapoma JR, Williams MA, Bhardwaj A, Ulatowski JA, Bederson J, Bullock R, Schmutzhard E, Pfausler B, Keyl PM, Tuhrim S, Hanley DF. Treatment of intraventricular hemorrhage with urokinase: effects on 30-Day survival. Stroke 2000;31(4):841–7.PubMedGoogle Scholar
  42. 42.
    Steiner L, Bergvall U, Zwetnow N. Quantitative estimation of intracerebral and intraventricular hematoma by computer tomography. Acta Radiol Suppl 1975;346:143–54.PubMedGoogle Scholar
  43. 43.
    Brott T, Broderick J, Kothari R, et al. Early hemorrhage growth in patients with intracerebral hemorrhage. Stroke 1997;28:1–5.PubMedGoogle Scholar
  44. 44.
    Fujii Y, Tanaka R, Takeuchi S, Koike T, Minakawa T, Sasaki O. Hematoma enlargement in spontaneous intracerebral hemorrhage. J Neurosurg 1994;80:51–7.PubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2007

Authors and Affiliations

  • Neeraj S. Naval
    • 1
  • Tamer A. Abdelhak
    • 1
  • Nathalie Urrunaga
    • 2
  • Paloma Zeballos
    • 2
  • Marek A. Mirski
    • 1
  • Juan R. Carhuapoma
    • 1
  1. 1.The Johns Hopkins HospitalBaltimoreUSA
  2. 2.Cayetano Heredia Peruvian UniversityLimaPeru

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