HEMORRHAGE EXPANSION IS ASSOCIATED WITH CLINICAL DETERIORATION

Intracerebral hemorrhage (ICH) is the deadliest form of acute stroke, with a mortality rate of 23-60%.^1-4 Most survivors suffer long-term neurologic deficits and are unable to return to independent levels of function.¹ The costs associated with this disease are tremendous, as well.^5-7 As the population continues to age and as the number of indications for long-term anticoagulation increase,⁸ the incidence of ICH is likely to rise. In fact, a recent article highlights a significant population increase in the incidence of this disease.⁹ Overall, the need for improved therapy has never been more urgent.

Hematoma formation causes injury by several mechanisms, including the development of perihematomal edema,^10,11 breakdown of the blood-brain barrier,¹² and release of glutamate, which causes neuronal excitation.¹³ However, the most significant factor is mass effect from the hematoma itself.^14,15 The neurological damage caused, as measured by poor functional outcome, is directly proportional to the volume of blood that extravasates from the ruptured vessel.¹⁶ This highlights the powerful impact of hematoma volume.

While hematoma formation was once considered to occur as a single event, more recent work has demonstrated that it can be a dynamic and progressive process. Continued bleeding is surprisingly common after presentation, highlighting a potential opportunity for intervention. One group examined over 100 patients with ICH who presented within 3 hours of symptom onset and found that 26% developed significant expansion (>33% of the initial volume) over the first hour.⁶ Another 12% of patients showed evidence of expansion over the next 20 hours, for a total of 38% who developed significant expansion.⁶ Another group found that 24% of patients who present acutely develop significant hematoma expansion within 24 hours after presentation.¹¹ Finally, after performing computerized planimetric analysis on hematoma volumes, one group found that 73% of patients who presented within 3 hours of symptom onset exhibited some degree of hematoma expansion within 24 hours.¹⁷

Hematoma expansion is devastating, and its development is associated with increased mortality and poor outcome. In one review of 627 patients, continued bleeding after presentation occurred in 14% of patients who presented within 24 hours of symptom onset. Mortality was increased in these patients, even after controlling for factors known to influence outcome.¹⁸ In a meta-analysis of 218 patients who presented within 3 hours of symptom onset, continued bleeding was associated with an increased risk of death and worse functional outcome in the survivors.¹⁷ This highlights a tremendous opportunity for intervention, as arresting such bleeding and preventing hematoma expansion may well decrease mortality and improve functional outcome.¹⁹

The pathophysiology of hematoma expansion is poorly understood. The original arterioles that ruptured may exhibit slow persistent bleeding; also, delayed rebleeding events can occur.^11,14,15 Alternatively, vascular injury induced by hematoma formation may lead to hemorrhage from new sources at the periphery of the hematoma.^16-23 Whatever the mechanism, hematoma expansion appears to be an independent predictor of both mortality and poor neurological outcome.^17,20

The finding that hematoma expansion predicts poor outcome highlights a tremendous opportunity for intervention. While various clinical features are associated with poor outcome,^2,18,21-23 many of these (eg, age, genetic risk factors, hematoma size on arrival) cannot be altered. Those that can potentially be managed include elevated blood pressure,^24-28 hyperglycemia on arrival,^{21, 29} and premorbid warfarin use,^1,16 although no studies have evaluated whether these interventions improve outcome.³⁰ Notably, high blood pressure,³¹ hyperglycemia,²⁹ and coagulopathy^1,16,32,33 specifically predict hematoma expansion, highlighting the possibility that these factors exert their effects on outcome by potentiating ongoing bleeding. As a result, these factors are often managed aggressively in the emergency department and intensive care unit. For example, the American Stroke Association recommends maintaining blood pressure lower than 180/105 mm Hg,³ and the European Stroke Initiative recommends a similar target for patients who have a history of hypertension.³⁴ In those patients taking oral anticoagulants, anticoagulation reversal is strongly recommended by the European Stroke Initiative and multiple experts,^34-39 with the explicit goal of minimizing hematoma expansion in this high-risk population.

Recognizing the possibility that reducing the risk of expansion may improve outcome, hemostatic agents have been tested for their ability to arrest ongoing bleeding and improve outcome.^40-43 The largest published study was a phase II trial of the hemostatic agent recombinant activated factor VII (rFVIIa). In this dose-ranging study, no individual dose improved outcome compared with the placebo group. However, when the different treatment groups were combined and compared with the placebo group, promising evidence emerged of a reduced risk of hematoma expansion, reduced mortality, and improved neurologic outcome.⁴¹ Concerns arose that an increased risk of thromboembolic adverse events may be associated with this agent,^44-47 and a phase III trial has recently been concluded to establish whether the benefit outweighs this risk.

In conclusion, patients with acute ICH often continue to bleed following presentation, offering the clinician a potential opportunity for intervention. Future trials evaluating the impact of blood pressure management, reversal of coagulopathy, and acute hemostatic therapy may show promise in arresting this bleeding. By preventing hematoma expansion, the clinician may not only improve neurologic outcome but also save lives.

REFERENCES

1. Rosand J, Eckman MH, Knudsen KA, et al. The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. Arch Intern Med. 2004;164:880-4.
2. Dixon AA, Holness RO, Howes WJ, Garner JB. Spontaneous intracerebral haemorrhage: an analysis of factors affecting prognosis. Can J Neurol Sci. 1985;12:267-71.
3. Broderick JP, Adams HP Jr, Barsan W, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: A statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke. 1999;30:905-15.
4. Qureshi AI, Tuhrim S, Broderick JP, et al. Spontaneous intracerebral hemorrhage. N Engl J Med. 2001;344:1450-60.
5. Russell MW, Joshi AV, Neumann PJ, et al. Predictors of hospital length of stay and cost in patients with intracerebral hemorrhage. Neurology. 2006;67:1279-81.
6. Earnshaw SR, Joshi AV, Wilson MR, Rosand J. Cost-effectiveness of recombinant activated factor VII in the treatment of intracerebral hemorrhage. Stroke. 2006;37:2751-8.
7. Weimar C, Weber C, Wagner M, et al. Management patterns and health care use after intracerebral hemorrhage. a cost-of-illness study from a societal perspective in Germany. Cerebrovasc Dis. 2003;15:29-36.
8. Ansell J, Hirsh J, Dalen J, et al. Managing oral anticoagulant therapy. Chest. 2001;119:22S-38S.
9. Flaherty ML, Kissela B, Woo D, et al. The increasing incidence of anticoagulant-associated intracerebral hemorrhage. Neurology. 2007;68:116-21.
10. Gebel JM Jr, Jauch EC, Brott TG, et al. Relative edema volume is a predictor of outcome in patients with hyperacute spontaneous intracerebral hemorrhage. Stroke. 2002;33:2636-41.
11. Gebel JM Jr, Jauch EC, Brott TG, et al. Natural history of perihematomal edema in patients with hyperacute spontaneous intracerebral hemorrhage. Stroke. 2002;33:2631-5.
12. Rosenberg GA, Navratil M. Metalloproteinase inhibition blocks edema in intracerebral hemorrhage in the rat. Neurology. 1997;48:921-6.
13. Ardizzone TD, Lu A, Wagner KR, et al. Glutamate receptor blockade attenuates glucose hypermetabolism in perihematomal brain after experimental intracerebral hemorrhage in rat. Stroke. 2004;35:2587-91.
14. Towfighi A, Greenberg SM, Rosand J. Treatment and prevention of primary intracerebral hemorrhage. Semin Neurol. 2005;25:445-52.
15. Xi G, Keep RF, Hoff JT. Mechanisms of brain injury after intracerebral haemorrhage. Lancet Neurol. 2006;5:53-63.
16. Flibotte JJ, Hagan N, O'Donnell J, et al. Warfarin, hematoma expansion, and outcome of intracerebral hemorrhage. Neurology. 2004;63:1059-64.
17. Davis SM, Broderick J, Hennerici M, et al. Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage. Neurology. 2006;66:1175-81.
18. Fujii Y, Takeuchi S, Sasaki O, et al. Multivariate analysis of predictors of hematoma enlargement in spontaneous intracerebral hemorrhage. Stroke. 1998;29:1160-6.
19. Mayer SA, Rincon F. Ultra-early hemostatic therapy for acute intracerebral hemorrhage. Semin Hematol. 2006;43:S70-6.
20. Fujii Y, Tanaka R, Takeuchi S, et al. Hematoma enlargement in spontaneous intracerebral hemorrhage. J Neurosurg. 1994;80:51-7.
21. Passero S, Ciacci G, Ulivelli M. The influence of diabetes and hyperglycemia on clinical course after intracerebral hemorrhage. Neurology. 2003;61:1351-6.
22. Arboix A, Massons J, Garcia-Eroles L, et al. Diabetes is an independent risk factor for in-hospital mortality from acute spontaneous intracerebral hemorrhage. Diabetes Care. 2000;23:1527-32.
23. Qureshi AI, Safdar K, Weil J, et al. Predictors of early deterioration and mortality in black Americans with spontaneous intracerebral hemorrhage. Stroke. 1995;26:1764-7.
24. Tuhrim S, Dambrosia JM, Price TR, et al. Prediction of intracerebral hemorrhage survival. Ann Neurol. 1988;24:258-63.
25. Dandapani BK, Suzuki S, Kelley RE, et al. Relation between blood pressure and outcome in intracerebral hemorrhage. Stroke. 1995;26:21-4.
26. Terayama Y, Tanahashi N, Fukuuchi Y, Gotoh F. Prognostic value of admission blood pressure in patients with intracerebral hemorrhage. Keio Cooperative Stroke Study. Stroke. 1997;28:1185-8.
27. Fogelholm R, Avikainen S, Murros K. Prognostic value and determinants of first-day mean arterial pressure in spontaneous supratentorial intracerebral hemorrhage. Stroke. 1997;28:1396-1400.
28. Fagan SC, Kozak A, Hill WD, et al. Hypertension after experimental cerebral ischemia: candesartan provides neurovascular protection. J Hypertens. 2006;24:535-9.
29. Broderick JP, Diringer MN, Hill MD, et al. Determinants of intracerebral hemorrhage growth. An exploratory analysis. Stroke. 2007 [in press].
30. Steiner T, Kaste M, Forsting M, et al. Recommendations for the management of intracranial haemorrhage - part I: spontaneous intracerebral haemorrhage. The European stroke initiative writing committee and the writing committee for the EUSI executive committee. Cerebrovasc Dis. 2006;22:294-316.
31. Ohwaki K, Yano E, Nagashima H, et al. Blood pressure management in acute intracerebral hemorrhage: relationship between elevated blood pressure and hematoma enlargement. Stroke. 2004;35:1364-7.
32. Radberg JA, Olsson JE, Radberg CT. Prognostic parameters in spontaneous intracerebral hematomas with special reference to anticoagulant treatment. Stroke. 1991;22:571-6.
33. Yasaka M, Minematsu K, Naritomi H, et al. Predisposing factors for enlargement of intracerebral hemorrhage in patients treated with warfarin. Thromb Haemost. 2003;89:278-83.
34. Steiner T, Kaste M, Forsting M, et al. Recommendations for the management of intracranial haemorrhage - part I: spontaneous intracerebral haemorrhage. The European Stroke Initiative Writing Committee and the Writing Committee for the EUSI Executive Committee. Cerebrovasc Dis. 2006;22:294-316.
35. Aguilar MI, Hart RG, Kase CS, et al. Treatment of warfarin-associated intracerebral hemorrhage: literature review and expert opinion. Mayo Clin Proc. 2007;82:82-92.
36. Steiner T, Rosand J, Diringer M. Intracerebral hemorrhage associated with oral anticoagulant therapy: current practices and unresolved questions. Stroke. 2006;37:256-62.
37. Goldstein JN, Thomas SH, Frontiero V, et al. Timing of fresh frozen plasma administration and rapid correction of coagulopathy in warfarin-related intracerebral hemorrhage. Stroke. 2006;37:151-5.
38. Huttner HB, Schellinger PD, Hartmann M, et al. Hematoma growth and outcome in treated neurocritical care patients with intracerebral hemorrhage related to oral anticoagulant therapy: comparison of acute treatment strategies using vitamin K, fresh frozen plasma, and prothrombin complex concentrates. Stroke. 2006;37:1465-70.
39. Hemphill JC 3rd. Treating warfarin-related intracerebral hemorrhage: is fresh frozen plasma enough? Stroke. 2006;37:6-7.
40. Mayer SA. Ultra-early hemostatic therapy for intracerebral hemorrhage. Stroke. 2003;34:224-9.
41. Mayer SA, Brun NC, Begtrup K, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med. 2005;352:777-85.
42. Sorimachi T, Fujii Y, Morita K, Tanaka R. Rapid administration of antifibrinolytics and strict blood pressure control for intracerebral hemorrhage. Neurosurgery. 2005;57:837-44.
43. Mayer SA, Brun NC, Broderick J, et al. Recombinant activated factor VII for acute intracerebral hemorrhage: US phase IIA trial. Neurocrit Care. 2006;4:206-14.
44. Greenberg SM. Is "compassionate use" compassionate? rFVIIa for intracerebral hemorrhage. Neurology. 2006;67:934-5.
45. Subramaniam S, Demchuk AM, Watson T, et al. Unexpected posthemorrhagic hydrocephalus in patients treated with rFVIIa. Neurology. 2006;67:1096.
46. Sugg RM, Gonzales NR, Matherne DE, et al. Myocardial injury in patients with intracerebral hemorrhage treated with recombinant factor VIIa. Neurology. 2006;67:1053-5.
47. O'Connell KA, Wood JJ, Wise RP, et al. Thromboembolic adverse events after use of recombinant human coagulation factor VIIa. JAMA. 2006;295:293-8.