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Advances in the Care of Patients With Intracerebral Hemorrhage
CONCISE REVIEW FOR CLINICIANS INTRACEREBRAL HEMORRHAGE
Advances in the Care of Patients With Intracerebral Hemorrhage KRISTINE M. THOMPSON, MD; SHARON Y. GERLACH, MD; H. KEELS S. JORN, MD; JAN M. LARSON, MD; THOMAS G. BROTT, MD; AND JULIA A. FILES, MD Intracerebral hemorrhage (ICH), which comprises 15% to 30% of all strokes, has an estimated incidence of 37,000 cases per year. One third of patients are actively bleeding when they present to the emergency department, and hematoma growth during the first hours after ICH onset is thought to be a prime determinant of clinical deterioration. Inflammation, as opposed to ischemia, also negatively affects patient condition. Recombinant activated factor VII is emerging as a potential first-line therapy, especially in warfarin-associated hemorrhage. Corticosteroid therapy is not supported by contemporary studies or by current management guidelines. Aggressive blood pressure reduction is under investigation. Surgical intervention has shown no statistically significant benefit over medical management for patients with ICH in general, although subgroup analysis in a large randomized trial suggested potential benefits from surgery for patients with lobar ICH. Not long ago, ICH was considered virtually untreatable. Diligent efforts in both bench and clinical research are generating hope for patients who experience this catastrophic event.
Mayo Clin Proc. 2007;82(8):987-990
ED = emergency department; FFP = fresh-frozen plasma; ICH = intracerebral hemorrhage; INR = international normalized ratio; PCC = prothrombin complex concentrate; rFVIIa = recombinant activated factor VII; STICH = Surgical Treatment in Intracerebral Haemorrhage
I
ntracerebral hemorrhage (ICH) is a devastating event. A large hemorrhage is nearly universally fatal, and patients who do survive are often completely incapacitated. The incidence of ICH is estimated at 37,000 cases annually,1 comprising 15% to 30% of all strokes. Intracerebral hemorrhage is the most lethal type of stroke, with an overall mortality of 40% to 50%.2 Until recently, this catastrophic illness was considered virtually untreatable, and attention was focused on prevention. However, recent advances in the understanding of the mechanisms of brain injury in ICH have resulted in promising possibilities for clinical intervention.
ing when they present to the ED. Furthermore, hematoma growth has been found to be an independent determinant of both mortality and functional outcome.5 Between 8% and 14% of all ICHs occur in patients receiving anticoagulant therapy, and these patients have a higher rate of rapid clinical deterioration.6 In the past, the goal of reversing the international normalized ratio (INR) in patients experiencing coagulopathy or in those taking warfarin was to prevent recurrence of bleeding. Because many of these patients have ongoing hemorrhage at presentation, rapid reversal is critical to limit hematoma expansion and clinical deterioration. Until recently, administration of fresh-frozen plasma (FFP) in combination with vitamin K was believed to be the fastest, most effective reversal strategy. However, emerging information suggests that prothrombin complex concentrates (PCCs) or recombinant activated factor VII (rFVIIa) may complement vitamin K in the urgent treatment of warfarin-associated ICH. Prothrombin complex concentrates have been used to treat warfarin-associated ICH in Europe for many years. They contain coagulation factors VII, X, XI, prothrombin, and proteins C and S in concentrated form. The dose depends on the factor XI content and can vary greatly among preparations. Studies have demonstrated that PCCs can normalize an INR more rapidly than FFP and do not require thawing or compatibility testing.7 Experts recommend concomitant administration of vitamin K. Thrombotic events have been reported with PCC infusion.8 Large, controlled trials are needed to quantify the risks and benefits of this potential therapy. Recombinant activated factor VII was developed as a treatment for hemophilic patients with antibodies to factors VIII and IX. It has been investigated as a treatment to control bleeding in major trauma and surgical catastrophes,
HEMATOMA CONTROL When a patient presents to the emergency department (ED) with ICH, the physician’s first priority is to stop the bleeding. Both clinical experience and scientific investigation have shown that larger hematoma volumes are associated with higher morbidity and mortality. In a population-based study, Broderick et al3 demonstrated that hematoma volume was the most accurate predictor of outcome (Figure 1). Using serial computed tomographic scans, Brott et al4 documented that up to 30% of patients are actively bleedMayo Clin Proc.
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From the Department of Emergency Medicine (K.M.T.), Division of Community Internal Medicine (S.Y.G., H.K.S.J.), Department of Family Medicine (J.M.L.), and Department of Neurology (T.G.B.), Mayo Clinic, Jacksonville, FL; and Division of Women’s Health Internal Medicine (J.A.F.), Mayo Clinic, Scottsdale, AZ. The Department of Neurology is reimbursed for Dr Brott’s services as Chair of the Data Monitoring Committee for the clinical trials of recombinant factor VIIa. A question-and-answer section appears at the end of this article. Individual reprints of this article are not available. Address correspondence to Kristine M. Thompson, MD, Department of Emergency Medicine, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224 ([email protected]). © 2007 Mayo Foundation for Medical Education and Research
August 2007;82(8):987-990
•
www.mayoclinicproceedings.com
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
987
Volume of ICH (cm3)
INTRACEREBRAL HEMORRHAGE
athy were released to the public by the manufacturer. The trial involved 821 patients from 22 countries who were confirmed by computed tomography to have spontaneous ICH. These patients were randomized to receive either rFVIIa or placebo within 4 hours of symptom onset. The treated group had less hematoma growth and improved clinical outcomes at 15 days. However, the primary end point of improved mortality and less severe disability at 90 days was not significantly different between the 2 groups.13
150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0
DAMAGE CONTROL 0
1
2
3
4
5
Dead
Condition at 30 d (Oxford Handicap Scale)
FIGURE 1. Plot shows 30-day outcomes for 162 patients with intracerebral hemorrhage (ICH) as measured by the modified Oxford Handicap Scale according to the volume of parenchymal hemorrhage: 0 = no symptoms; 1 = minor symptoms that do not interfere with lifestyle; 2 = minor handicap; 3 = moderate handicap; 4 = moderately severe handicap; and 5 = severe handicap. From Stroke,3 with permission.
raising the possibility of its usefulness in other devastating forms of hemorrhage.9 It has a half-life of 2.3 hours,10 effectively reverses an elevated INR, and accelerates coagulation in patients with normal ratios.11,12 Freeman et al11 demonstrated the rapid normalization of INR in warfarin-related brain hemorrhage in 1 of the first reported clinical investigations of the use of rFVIIa in ICH. The rapidity with which rFVIIa normalizes INR makes it ideally suited for facilitating neurosurgical intervention and potentially limiting hematoma growth. However, the duration of the effect of rFVIIa has yet to be defined. Experience has shown that the effects of warfarin last longer than those of rFVIIa, necessitating the simultaneous administration of FFP and vitamin K. The most effective dosing and timing of these agents remain an active area of investigation. The promise shown by rFVIIa in treating spontaneous ICH is not limited to anticoagulation or coagulopathy. Mayer et al12 published encouraging results from a phase 2 trial in which 399 patients with spontaneous ICH were randomized to receive placebo or 1 of 3 doses of rFVIIa within 3 hours of symptom onset. Overall, patients who received rFVIIa had less hematoma growth, less edema, and smaller total lesion volume (blood plus surrounding edema) compared with those who received placebo. The treated group had a 38% relative reduction in mortality and a dose-related trend toward improved morbidity. However, complications, including acute myocardial infarction and ischemic stroke, occurred more frequently in treated patients. On February 26, 2007, the results of the phase 3 trial investigating the use of rFVIIa in ICH without coagulop988
Mayo Clin Proc.
•
The pathophysiology of brain injury in ICH remains a topic of debate. Perihematomal injury is widely agreed to result in edema and mass effect, producing the observed clinical deterioration seen in many of these patients. However, the mechanisms of injury are not well understood. Previously, swelling of the tissue was hypothesized to lead to a mechanical, localized infarction of brain parenchyma.14,15 These ischemic areas were believed to stimulate the body’s inflammatory cascade, producing vasogenic edema. In an attempt to visually demonstrate this phenomenon, Powers et al16 used positron emission tomographic scanning to evaluate the blood flow to the perihematomal tissue. Surprisingly, the images showed that the blood flow to these areas was unchanged. Ischemia may not be the prevailing trigger for the massive perihematomal inflammatory response seen after an acute ICH. The prevailing theory is that coagulation end products activate the inflammatory cascade leading to vasogenic edema, cytotoxic edema, and disruption of the blood-brain barrier, amplifying the damage caused by the primary hematoma.17 Although treatment with corticosteroids was proposed as a logical management option, early clinical trials of the value of dexamethasone administration in patients with acute stroke have failed to demonstrate efficacy.18-22 In fact, a randomized controlled trial was terminated early because the dexamethasone group had a significantly higher rate of complications, such as infection and hyperglycemia, in the absence of clinical benefit.23 A 2005 Cochrane comprehensive review on the use of corticosteroids for aneurysmal subarachnoid hemorrhage and primary ICH found insufficient evidence to draw any meaningful conclusions.24 Accordingly, treatment of patients with ICH with corticosteroids cannot be recommended at this time. As the understanding of the mechanism of injury shifts from ischemia to inflammation, management of blood pressure in ICH patients may also change. Historically, physicians have taken care not to lower blood pressure too aggressively because rapidly lowering blood pressure may increase the area of ischemia. This caution was justifiable when perihematomal ischemia was believed to lead to in-
August 2007;82(8):987-990
•
www.mayoclinicproceedings.com
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
INTRACEREBRAL HEMORRHAGE
creased morbidity. However, studies examining autoregulation and cerebral perfusion after blood pressure reduction in ICH have shown no significant change in blood flow if the pressure is lowered by 20% or less in the acute phase.25 These findings are consistent with the American Heart Association recommendation to maintain mean arterial pressure below 130 mm Hg in patients with acute ICH.1 Now that the inflammatory cascade, rather than ischemia, may be an important determinant of outcome, aggressive blood pressure management may actually be helpful. This hypothesis has not been rigorously tested and represents an opportunity for future investigation. Intuitively, surgical evacuation of the hematoma would give patients the best chance for favorable outcome. Indeed, in the early 1990s, rapid surgical intervention became the focus of investigation in acute ICH. However, this benefit has not been demonstrated. In studies by Morgenstern et al26 and Zuccarello et al,27 surgical evacuation for ICH initiated within hours of onset did not improve outcome. The International Surgical Treatment in Intracerebral Haemorrhage (STICH) trial randomized 1033 patients to early surgical hematoma evacuation vs conservative therapy.28 The STICH authors28 reported no statistically significant difference between the 2 approaches with regard to mortality or morbidity. Because the study had several limitations, some questions remain. A subgroup analysis suggested that patients with lobar hematomas located 1 cm or less from the cortical surface may be more likely to have a favorable outcome with early surgical treatment. However, the authors themselves questioned the statistical significance of this finding. The STICH II trial, designed to investigate medical vs surgical management of these lobar hemorrhages, is under way. Because surgical removal of the hematoma does not appear to universally improve outcome, investigation into other methods of controlling the toxicity of blood components is warranted. Red blood cells and their contents are resorbed slowly for several days to several weeks, exposing the brain parenchyma to toxicity for a prolonged interval. Several investigators are examining potential pharmacologic therapies that would protect brain cells from the toxic effects of a resolving hematoma.29 Hyperosmolar therapy in the form of mannitol or hypertonic saline is occasionally used to treat ICH. Although this treatment has not yet been evaluated by a randomized, blinded, controlled trial, a recent study30 did find improved outcomes in patients with impending herniation who were treated with osmotic agents. As such, hyperosmolar therapy remains an option in patients with signs of mass effect, herniation, or both. The publication of 2 articles reporting improved neurologic outcome after cardiac arrest has revitalized interest in Mayo Clin Proc.
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the use of induced hypothermia as a neuroprotective agent in acute stroke.31,32 The use of hypothermia for treatment of ICH was reported as early as 1956.33 Multiple laboratory experiments using animal models have shown that lowering the core temperature protects the blood-brain barrier through various cellular and biochemical mechanisms. However, complications have been reported in clinical trials of surfacecooling techniques, including infectious complications, clotting abnormalities, cardiac arrhythmias, and difficulty in rapidly achieving target temperatures.34 Localized brain cooling has been proposed as an alternative to whole-body cooling for patients with neurologic insults. A recent study using a porcine model of ICH demonstrated decreased blood-brain barrier permeability and a marked reduction in vasogenic edema with localized brain cooling.35 Clinical trials of the value of induced hypothermia for neuroprotection are needed to identify appropriate candidates, optimal target temperatures, and the ideal duration of therapy. CONCLUSIONS Intracerebral hemorrhage is a catastrophic event with high morbidity and mortality. Patients may still be actively bleeding at presentation, necessitating rapid reversal of anticoagulation. The emergence of rFVIIa as a potential treatment of ongoing bleeding has shown promise for patients with warfarin-related ICH, an increasingly common public health problem. The negative results of the phase 3 study of rFVIIa for patients with ICH who did not have coagulation defects are disappointing. Detailed analysis of those results has not been completed, however, and so inference at this time should be tentative. New experimental and clinical studies of the interaction between blood pressure and cerebral edema may lead us to rethink the management of blood pressure. The first STICH trial, evaluating early surgical intervention, did not demonstrate a benefit of surgery over medical management. The STICH II trial is already under way to investigate medical vs surgical management of lobar hemorrhages. Induced hypothermia has reemerged as a potential neuroprotective agent. Because of diligent efforts in both bench and clinical research, hope is emerging in the treatment of ICH, a catastrophic event that was not long ago thought to be virtually untreatable. REFERENCES 1. 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;30:905-915. 2. Frankowski RF. Epidemiology of stroke and intracerebral hemorrhage. In: Kaufman HH, ed. Intracerebral Hematomas. New York, NY: Raven Press; 1992:1-11. 3. Broderick JP, Brott TG, Duldner JE, Tomsick T, Huster G. Volume of intracerebral hemorrhage: a powerful and easy-to-use predictor of 30-day mortality. Stroke. 1993;24:987-993.
August 2007;82(8):987-990
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www.mayoclinicproceedings.com
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
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4. Brott T, Broderick J, Kothari R, et al. Early hemorrhage growth in patients with intracerebral hemorrhage. Stroke. 1997;28:1-5. 5. Davis SM, Broderick J, Hennerici M, et al, Recombinant Activated Factor VII Intracerebral Hemorrhage Trial Investigators. Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage. Neurology. 2006;66:1175-1181. 6. Sjoblom L, Hardemark HG, Lindgren A, et al. Management and prognostic features of intracerebral hemorrhage during anticoagulant therapy: a Swedish multicenter study. Stroke. 2001;32:2567-2574. 7. Makris M, Greaves M, Phillips WS, Kitchen S, Rosendaal FR, Preston EF. Emergency oral anticoagulant reversal: the relative efficacy of infusions of fresh frozen plasma and clotting factor concentrate on correction of the coagulopathy. Thromb Haemost. 1997;77:477-480. 8. Aguilar MI, Hart RG, Kase CS, et al. Treatment of warfarin-associated intracerebral hemorrhage: literature review and expert opinion [published correction appears in Mayo Clin Proc. 2007;82:387]. Mayo Clin Proc. 2007;82: 82-92. 9. Martinowitz U, Kenet G, Segal E, et al. Recombinant activated factor VII for adjunctive hemorrhage control in trauma. J Trauma. 2001;51:431-438. 10. NovoSeven [package insert]. Princeton, NJ: Novo Nordisk, Inc; 2006. 11. Freeman WD, Brott TG, Barrett KM, et al. Recombinant factor VIIa for rapid reversal of warfarin anticoagulation in acute intracranial hemorrhage. Mayo Clin Proc. 2004;79:1495-1500. 12. Mayer SA, Brun NC, Begtrup K, et al, Recombinant Activated Factor VII Intracerebral Hemorrhage Trial Investigators. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med. 2005;352:777-785. 13. Novo Nordisk A/S. Stock exchange announcement no. 5/2007. February 26, 2007. Available at: www.novonordisk.com/investors/sea/sea.asp?sShow NewsItemGuID=0cfc120c-f013-4ad6-9130-55227465e3e8&sShowLanguageCode =en-GB&sSearchText=Cardiac+surgery. Accessed April 3, 2007. 14. Nath FP, Jenkins A, Mendelow AD, Graham DI, Teasdale GM. Early hemodynamic changes in experimental intracerebral hemorrhage. J Neurosurg. 1986;65:697-703. 15. Bullock R, Brock-Utne J, van Dellen J, Blake G. Intracerebral hemorrhage in a primate model: effect on regional cerebral blood flow. Surg Neurol. 1988;29:101-107. 16. Powers WJ, Zazulia AR, Videen TO, et al. Autoregulation of cerebral blood flow surrounding acute (6 to 22 hours) intracerebral hemorrhage. Neurology. 2001;57:18-24. 17. Qureshi AI, Tuhrim S, Broderick JP, Batjer HH, Hondo H, Hanley DF. Spontaneous intracerebral hemorrhage. N Engl J Med. 2001;344:1450-1460. 18. Bauer RB, Tellez H. Dexamethasone as treatment in cerebrovascular disease, 2: a controlled study in acute cerebral infarction. Stroke. 1973;4:547-555. 19. Norris JW. Steroid therapy in acute cerebral infarction. Arch Neurol. 1976; 33:69-71. 20. Dyken M, White PT. Evaluation of cortisone in the treatment of cerebral infarction. JAMA. 1956:1531-1534. 21. Mulley G, Wilcox RG, Mitchell JR. Dexamethasone in acute stroke. Br Med J. 1978;2:994-996. 22. Norris JW, Hachinski VC. High dose steroid treatment in cerebral infarction. Br Med J (Clin Res Ed). 1986;292:21-23. 23. Poungvarin N, Bhoopat W, Viriyavejakul A, et al. Effects of dexamethasone in primary supratentorial intracerebral hemorrhage. N Engl J Med. 1987; 316:1229-1233. 24. Feigin VL, Anderson N, Rinkel GJ, Algra A, van Gijn J, Bennett DA. Corticosteroids for aneurysmal subarachnoid haemorrhage and primary intracerebral haemorrhage. Cochrane Database Syst Rev. 2005;(3):CD004583. 25. Rasool AH, Rahman AR, Choudhury SR, Singh RB. Blood pressure in acute intracerebral haemorrhage. J Hum Hypertens. 2004;18:187-192. 26. Morgenstern LB, Frankowski RF, Shedden P, Pasteur W, Grotta JC. Surgical treatment for intracerebral hemorrhage (STICH): a single-center, randomized clinical trial. Neurology. 1998;51:1359-1363. 27. Zuccarello M, Brott T, Derex L, et al. Early surgical treatment for supratentorial intracerebral hemorrhage: a randomized feasibility study. Stroke. 1999;30:1833-1839. 28. Mendelow AD, Gregson BA, Fernandes HM, et al, STICH Investigators. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trial. Lancet. 2005; 365:387-397. 29. Wagner KR, Dwyer BE. Hematoma removal, heme, and heme oxygenase following hemorrhagic stroke. Ann N Y Acad Sci. 2004;1012:237-251. 30. Qureshi AI, Geocadin RG, Suarez JI, Ulatowski JA. Long-term outcome after medical reversal of transtentorial herniation in patients with supratentorial mass lesions. Crit Care Med. 2000;28:1556-1564. 31. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346:557-563.
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32. Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest [published correction appears in N Engl J Med. 2002;346:1756]. N Engl J Med. 2002;346: 549-556. 33. Howell DA, Posnikoff J, Stratford JG. Prolonged hypothermia in treatment of massive cerebral haemorrhage: a preliminary report. Can Med Assoc J. 1956;75:388-394. 34. Wijdicks EF. Induced hypothermia in neurocatastrophes: feeling the chill. Rev Neurol Dis. 2004;1:10-15. 35. Wagner KR, Zuccarello M. Local brain hypothermia for neuroprotection in stroke treatment and aneurysm repair. Neurol Res. 2005;27:238-245.
Questions About ICH 1. Which one of the following most closely approximates the incidence of ICH? a. 37,000 cases per year b. 25,000 cases per year c. 11,000 cases per year d. 85,000 cases per year e. 50,000 cases per year 2. Which one of the following most closely represents the percentage of patients with ICH who are actively bleeding when they present to the ED? a. 10% b. 30% c. 5% d. 50% e. 1% 3. Which one of the following is the most accurate predictor of outcome in patients who have ICH? a. Hematoma volume b. Rate of hematoma growth c. Neurologic examination on presentation d. Time from onset to presentation e. INR at presentation 4. In which one of the following ways does hypothermia benefit patients with ICH? a. Induces shivering b. Produces bradycardia c. Stimulates the clotting cascade d. Protects the blood-brain barrier e. Maintains sedation 5. Which one of the following is the most likely cause of secondary cellular injury in ICH? a. Ischemia b. Inflammation c. Low blood pressure d. Edema e. Toxins
Correct answers: 1. a, 2. b, 3. a, 4. d, 5. b
August 2007;82(8):987-990
•
www.mayoclinicproceedings.com
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Advances in the Care of Patients With Intracerebral Hemorrhage KRISTINE M. THOMPSON, MD; SHARON Y. GERLACH, MD; H. KEELS S. JORN, MD; JAN M. LARSON, MD; THOMAS G. BROTT, MD; AND JULIA A. FILES, MD Intracerebral hemorrhage (ICH), which comprises 15% to 30% of all strokes, has an estimated incidence of 37,000 cases per year. One third of patients are actively bleeding when they present to the emergency department, and hematoma growth during the first hours after ICH onset is thought to be a prime determinant of clinical deterioration. Inflammation, as opposed to ischemia, also negatively affects patient condition. Recombinant activated factor VII is emerging as a potential first-line therapy, especially in warfarin-associated hemorrhage. Corticosteroid therapy is not supported by contemporary studies or by current management guidelines. Aggressive blood pressure reduction is under investigation. Surgical intervention has shown no statistically significant benefit over medical management for patients with ICH in general, although subgroup analysis in a large randomized trial suggested potential benefits from surgery for patients with lobar ICH. Not long ago, ICH was considered virtually untreatable. Diligent efforts in both bench and clinical research are generating hope for patients who experience this catastrophic event.
Mayo Clin Proc. 2007;82(8):987-990
ED = emergency department; FFP = fresh-frozen plasma; ICH = intracerebral hemorrhage; INR = international normalized ratio; PCC = prothrombin complex concentrate; rFVIIa = recombinant activated factor VII; STICH = Surgical Treatment in Intracerebral Haemorrhage
I
ntracerebral hemorrhage (ICH) is a devastating event. A large hemorrhage is nearly universally fatal, and patients who do survive are often completely incapacitated. The incidence of ICH is estimated at 37,000 cases annually,1 comprising 15% to 30% of all strokes. Intracerebral hemorrhage is the most lethal type of stroke, with an overall mortality of 40% to 50%.2 Until recently, this catastrophic illness was considered virtually untreatable, and attention was focused on prevention. However, recent advances in the understanding of the mechanisms of brain injury in ICH have resulted in promising possibilities for clinical intervention.
ing when they present to the ED. Furthermore, hematoma growth has been found to be an independent determinant of both mortality and functional outcome.5 Between 8% and 14% of all ICHs occur in patients receiving anticoagulant therapy, and these patients have a higher rate of rapid clinical deterioration.6 In the past, the goal of reversing the international normalized ratio (INR) in patients experiencing coagulopathy or in those taking warfarin was to prevent recurrence of bleeding. Because many of these patients have ongoing hemorrhage at presentation, rapid reversal is critical to limit hematoma expansion and clinical deterioration. Until recently, administration of fresh-frozen plasma (FFP) in combination with vitamin K was believed to be the fastest, most effective reversal strategy. However, emerging information suggests that prothrombin complex concentrates (PCCs) or recombinant activated factor VII (rFVIIa) may complement vitamin K in the urgent treatment of warfarin-associated ICH. Prothrombin complex concentrates have been used to treat warfarin-associated ICH in Europe for many years. They contain coagulation factors VII, X, XI, prothrombin, and proteins C and S in concentrated form. The dose depends on the factor XI content and can vary greatly among preparations. Studies have demonstrated that PCCs can normalize an INR more rapidly than FFP and do not require thawing or compatibility testing.7 Experts recommend concomitant administration of vitamin K. Thrombotic events have been reported with PCC infusion.8 Large, controlled trials are needed to quantify the risks and benefits of this potential therapy. Recombinant activated factor VII was developed as a treatment for hemophilic patients with antibodies to factors VIII and IX. It has been investigated as a treatment to control bleeding in major trauma and surgical catastrophes,
HEMATOMA CONTROL When a patient presents to the emergency department (ED) with ICH, the physician’s first priority is to stop the bleeding. Both clinical experience and scientific investigation have shown that larger hematoma volumes are associated with higher morbidity and mortality. In a population-based study, Broderick et al3 demonstrated that hematoma volume was the most accurate predictor of outcome (Figure 1). Using serial computed tomographic scans, Brott et al4 documented that up to 30% of patients are actively bleedMayo Clin Proc.
•
From the Department of Emergency Medicine (K.M.T.), Division of Community Internal Medicine (S.Y.G., H.K.S.J.), Department of Family Medicine (J.M.L.), and Department of Neurology (T.G.B.), Mayo Clinic, Jacksonville, FL; and Division of Women’s Health Internal Medicine (J.A.F.), Mayo Clinic, Scottsdale, AZ. The Department of Neurology is reimbursed for Dr Brott’s services as Chair of the Data Monitoring Committee for the clinical trials of recombinant factor VIIa. A question-and-answer section appears at the end of this article. Individual reprints of this article are not available. Address correspondence to Kristine M. Thompson, MD, Department of Emergency Medicine, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224 ([email protected]). © 2007 Mayo Foundation for Medical Education and Research
August 2007;82(8):987-990
•
www.mayoclinicproceedings.com
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
987
Volume of ICH (cm3)
INTRACEREBRAL HEMORRHAGE
athy were released to the public by the manufacturer. The trial involved 821 patients from 22 countries who were confirmed by computed tomography to have spontaneous ICH. These patients were randomized to receive either rFVIIa or placebo within 4 hours of symptom onset. The treated group had less hematoma growth and improved clinical outcomes at 15 days. However, the primary end point of improved mortality and less severe disability at 90 days was not significantly different between the 2 groups.13
150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0
DAMAGE CONTROL 0
1
2
3
4
5
Dead
Condition at 30 d (Oxford Handicap Scale)
FIGURE 1. Plot shows 30-day outcomes for 162 patients with intracerebral hemorrhage (ICH) as measured by the modified Oxford Handicap Scale according to the volume of parenchymal hemorrhage: 0 = no symptoms; 1 = minor symptoms that do not interfere with lifestyle; 2 = minor handicap; 3 = moderate handicap; 4 = moderately severe handicap; and 5 = severe handicap. From Stroke,3 with permission.
raising the possibility of its usefulness in other devastating forms of hemorrhage.9 It has a half-life of 2.3 hours,10 effectively reverses an elevated INR, and accelerates coagulation in patients with normal ratios.11,12 Freeman et al11 demonstrated the rapid normalization of INR in warfarin-related brain hemorrhage in 1 of the first reported clinical investigations of the use of rFVIIa in ICH. The rapidity with which rFVIIa normalizes INR makes it ideally suited for facilitating neurosurgical intervention and potentially limiting hematoma growth. However, the duration of the effect of rFVIIa has yet to be defined. Experience has shown that the effects of warfarin last longer than those of rFVIIa, necessitating the simultaneous administration of FFP and vitamin K. The most effective dosing and timing of these agents remain an active area of investigation. The promise shown by rFVIIa in treating spontaneous ICH is not limited to anticoagulation or coagulopathy. Mayer et al12 published encouraging results from a phase 2 trial in which 399 patients with spontaneous ICH were randomized to receive placebo or 1 of 3 doses of rFVIIa within 3 hours of symptom onset. Overall, patients who received rFVIIa had less hematoma growth, less edema, and smaller total lesion volume (blood plus surrounding edema) compared with those who received placebo. The treated group had a 38% relative reduction in mortality and a dose-related trend toward improved morbidity. However, complications, including acute myocardial infarction and ischemic stroke, occurred more frequently in treated patients. On February 26, 2007, the results of the phase 3 trial investigating the use of rFVIIa in ICH without coagulop988
Mayo Clin Proc.
•
The pathophysiology of brain injury in ICH remains a topic of debate. Perihematomal injury is widely agreed to result in edema and mass effect, producing the observed clinical deterioration seen in many of these patients. However, the mechanisms of injury are not well understood. Previously, swelling of the tissue was hypothesized to lead to a mechanical, localized infarction of brain parenchyma.14,15 These ischemic areas were believed to stimulate the body’s inflammatory cascade, producing vasogenic edema. In an attempt to visually demonstrate this phenomenon, Powers et al16 used positron emission tomographic scanning to evaluate the blood flow to the perihematomal tissue. Surprisingly, the images showed that the blood flow to these areas was unchanged. Ischemia may not be the prevailing trigger for the massive perihematomal inflammatory response seen after an acute ICH. The prevailing theory is that coagulation end products activate the inflammatory cascade leading to vasogenic edema, cytotoxic edema, and disruption of the blood-brain barrier, amplifying the damage caused by the primary hematoma.17 Although treatment with corticosteroids was proposed as a logical management option, early clinical trials of the value of dexamethasone administration in patients with acute stroke have failed to demonstrate efficacy.18-22 In fact, a randomized controlled trial was terminated early because the dexamethasone group had a significantly higher rate of complications, such as infection and hyperglycemia, in the absence of clinical benefit.23 A 2005 Cochrane comprehensive review on the use of corticosteroids for aneurysmal subarachnoid hemorrhage and primary ICH found insufficient evidence to draw any meaningful conclusions.24 Accordingly, treatment of patients with ICH with corticosteroids cannot be recommended at this time. As the understanding of the mechanism of injury shifts from ischemia to inflammation, management of blood pressure in ICH patients may also change. Historically, physicians have taken care not to lower blood pressure too aggressively because rapidly lowering blood pressure may increase the area of ischemia. This caution was justifiable when perihematomal ischemia was believed to lead to in-
August 2007;82(8):987-990
•
www.mayoclinicproceedings.com
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
INTRACEREBRAL HEMORRHAGE
creased morbidity. However, studies examining autoregulation and cerebral perfusion after blood pressure reduction in ICH have shown no significant change in blood flow if the pressure is lowered by 20% or less in the acute phase.25 These findings are consistent with the American Heart Association recommendation to maintain mean arterial pressure below 130 mm Hg in patients with acute ICH.1 Now that the inflammatory cascade, rather than ischemia, may be an important determinant of outcome, aggressive blood pressure management may actually be helpful. This hypothesis has not been rigorously tested and represents an opportunity for future investigation. Intuitively, surgical evacuation of the hematoma would give patients the best chance for favorable outcome. Indeed, in the early 1990s, rapid surgical intervention became the focus of investigation in acute ICH. However, this benefit has not been demonstrated. In studies by Morgenstern et al26 and Zuccarello et al,27 surgical evacuation for ICH initiated within hours of onset did not improve outcome. The International Surgical Treatment in Intracerebral Haemorrhage (STICH) trial randomized 1033 patients to early surgical hematoma evacuation vs conservative therapy.28 The STICH authors28 reported no statistically significant difference between the 2 approaches with regard to mortality or morbidity. Because the study had several limitations, some questions remain. A subgroup analysis suggested that patients with lobar hematomas located 1 cm or less from the cortical surface may be more likely to have a favorable outcome with early surgical treatment. However, the authors themselves questioned the statistical significance of this finding. The STICH II trial, designed to investigate medical vs surgical management of these lobar hemorrhages, is under way. Because surgical removal of the hematoma does not appear to universally improve outcome, investigation into other methods of controlling the toxicity of blood components is warranted. Red blood cells and their contents are resorbed slowly for several days to several weeks, exposing the brain parenchyma to toxicity for a prolonged interval. Several investigators are examining potential pharmacologic therapies that would protect brain cells from the toxic effects of a resolving hematoma.29 Hyperosmolar therapy in the form of mannitol or hypertonic saline is occasionally used to treat ICH. Although this treatment has not yet been evaluated by a randomized, blinded, controlled trial, a recent study30 did find improved outcomes in patients with impending herniation who were treated with osmotic agents. As such, hyperosmolar therapy remains an option in patients with signs of mass effect, herniation, or both. The publication of 2 articles reporting improved neurologic outcome after cardiac arrest has revitalized interest in Mayo Clin Proc.
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the use of induced hypothermia as a neuroprotective agent in acute stroke.31,32 The use of hypothermia for treatment of ICH was reported as early as 1956.33 Multiple laboratory experiments using animal models have shown that lowering the core temperature protects the blood-brain barrier through various cellular and biochemical mechanisms. However, complications have been reported in clinical trials of surfacecooling techniques, including infectious complications, clotting abnormalities, cardiac arrhythmias, and difficulty in rapidly achieving target temperatures.34 Localized brain cooling has been proposed as an alternative to whole-body cooling for patients with neurologic insults. A recent study using a porcine model of ICH demonstrated decreased blood-brain barrier permeability and a marked reduction in vasogenic edema with localized brain cooling.35 Clinical trials of the value of induced hypothermia for neuroprotection are needed to identify appropriate candidates, optimal target temperatures, and the ideal duration of therapy. CONCLUSIONS Intracerebral hemorrhage is a catastrophic event with high morbidity and mortality. Patients may still be actively bleeding at presentation, necessitating rapid reversal of anticoagulation. The emergence of rFVIIa as a potential treatment of ongoing bleeding has shown promise for patients with warfarin-related ICH, an increasingly common public health problem. The negative results of the phase 3 study of rFVIIa for patients with ICH who did not have coagulation defects are disappointing. Detailed analysis of those results has not been completed, however, and so inference at this time should be tentative. New experimental and clinical studies of the interaction between blood pressure and cerebral edema may lead us to rethink the management of blood pressure. The first STICH trial, evaluating early surgical intervention, did not demonstrate a benefit of surgery over medical management. The STICH II trial is already under way to investigate medical vs surgical management of lobar hemorrhages. Induced hypothermia has reemerged as a potential neuroprotective agent. Because of diligent efforts in both bench and clinical research, hope is emerging in the treatment of ICH, a catastrophic event that was not long ago thought to be virtually untreatable. REFERENCES 1. 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;30:905-915. 2. Frankowski RF. Epidemiology of stroke and intracerebral hemorrhage. In: Kaufman HH, ed. Intracerebral Hematomas. New York, NY: Raven Press; 1992:1-11. 3. Broderick JP, Brott TG, Duldner JE, Tomsick T, Huster G. Volume of intracerebral hemorrhage: a powerful and easy-to-use predictor of 30-day mortality. Stroke. 1993;24:987-993.
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4. Brott T, Broderick J, Kothari R, et al. Early hemorrhage growth in patients with intracerebral hemorrhage. Stroke. 1997;28:1-5. 5. Davis SM, Broderick J, Hennerici M, et al, Recombinant Activated Factor VII Intracerebral Hemorrhage Trial Investigators. Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage. Neurology. 2006;66:1175-1181. 6. Sjoblom L, Hardemark HG, Lindgren A, et al. Management and prognostic features of intracerebral hemorrhage during anticoagulant therapy: a Swedish multicenter study. Stroke. 2001;32:2567-2574. 7. Makris M, Greaves M, Phillips WS, Kitchen S, Rosendaal FR, Preston EF. Emergency oral anticoagulant reversal: the relative efficacy of infusions of fresh frozen plasma and clotting factor concentrate on correction of the coagulopathy. Thromb Haemost. 1997;77:477-480. 8. Aguilar MI, Hart RG, Kase CS, et al. Treatment of warfarin-associated intracerebral hemorrhage: literature review and expert opinion [published correction appears in Mayo Clin Proc. 2007;82:387]. Mayo Clin Proc. 2007;82: 82-92. 9. Martinowitz U, Kenet G, Segal E, et al. Recombinant activated factor VII for adjunctive hemorrhage control in trauma. J Trauma. 2001;51:431-438. 10. NovoSeven [package insert]. Princeton, NJ: Novo Nordisk, Inc; 2006. 11. Freeman WD, Brott TG, Barrett KM, et al. Recombinant factor VIIa for rapid reversal of warfarin anticoagulation in acute intracranial hemorrhage. Mayo Clin Proc. 2004;79:1495-1500. 12. Mayer SA, Brun NC, Begtrup K, et al, Recombinant Activated Factor VII Intracerebral Hemorrhage Trial Investigators. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med. 2005;352:777-785. 13. Novo Nordisk A/S. Stock exchange announcement no. 5/2007. February 26, 2007. Available at: www.novonordisk.com/investors/sea/sea.asp?sShow NewsItemGuID=0cfc120c-f013-4ad6-9130-55227465e3e8&sShowLanguageCode =en-GB&sSearchText=Cardiac+surgery. Accessed April 3, 2007. 14. Nath FP, Jenkins A, Mendelow AD, Graham DI, Teasdale GM. Early hemodynamic changes in experimental intracerebral hemorrhage. J Neurosurg. 1986;65:697-703. 15. Bullock R, Brock-Utne J, van Dellen J, Blake G. Intracerebral hemorrhage in a primate model: effect on regional cerebral blood flow. Surg Neurol. 1988;29:101-107. 16. Powers WJ, Zazulia AR, Videen TO, et al. Autoregulation of cerebral blood flow surrounding acute (6 to 22 hours) intracerebral hemorrhage. Neurology. 2001;57:18-24. 17. Qureshi AI, Tuhrim S, Broderick JP, Batjer HH, Hondo H, Hanley DF. Spontaneous intracerebral hemorrhage. N Engl J Med. 2001;344:1450-1460. 18. Bauer RB, Tellez H. Dexamethasone as treatment in cerebrovascular disease, 2: a controlled study in acute cerebral infarction. Stroke. 1973;4:547-555. 19. Norris JW. Steroid therapy in acute cerebral infarction. Arch Neurol. 1976; 33:69-71. 20. Dyken M, White PT. Evaluation of cortisone in the treatment of cerebral infarction. JAMA. 1956:1531-1534. 21. Mulley G, Wilcox RG, Mitchell JR. Dexamethasone in acute stroke. Br Med J. 1978;2:994-996. 22. Norris JW, Hachinski VC. High dose steroid treatment in cerebral infarction. Br Med J (Clin Res Ed). 1986;292:21-23. 23. Poungvarin N, Bhoopat W, Viriyavejakul A, et al. Effects of dexamethasone in primary supratentorial intracerebral hemorrhage. N Engl J Med. 1987; 316:1229-1233. 24. Feigin VL, Anderson N, Rinkel GJ, Algra A, van Gijn J, Bennett DA. Corticosteroids for aneurysmal subarachnoid haemorrhage and primary intracerebral haemorrhage. Cochrane Database Syst Rev. 2005;(3):CD004583. 25. Rasool AH, Rahman AR, Choudhury SR, Singh RB. Blood pressure in acute intracerebral haemorrhage. J Hum Hypertens. 2004;18:187-192. 26. Morgenstern LB, Frankowski RF, Shedden P, Pasteur W, Grotta JC. Surgical treatment for intracerebral hemorrhage (STICH): a single-center, randomized clinical trial. Neurology. 1998;51:1359-1363. 27. Zuccarello M, Brott T, Derex L, et al. Early surgical treatment for supratentorial intracerebral hemorrhage: a randomized feasibility study. Stroke. 1999;30:1833-1839. 28. Mendelow AD, Gregson BA, Fernandes HM, et al, STICH Investigators. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trial. Lancet. 2005; 365:387-397. 29. Wagner KR, Dwyer BE. Hematoma removal, heme, and heme oxygenase following hemorrhagic stroke. Ann N Y Acad Sci. 2004;1012:237-251. 30. Qureshi AI, Geocadin RG, Suarez JI, Ulatowski JA. Long-term outcome after medical reversal of transtentorial herniation in patients with supratentorial mass lesions. Crit Care Med. 2000;28:1556-1564. 31. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346:557-563.
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32. Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest [published correction appears in N Engl J Med. 2002;346:1756]. N Engl J Med. 2002;346: 549-556. 33. Howell DA, Posnikoff J, Stratford JG. Prolonged hypothermia in treatment of massive cerebral haemorrhage: a preliminary report. Can Med Assoc J. 1956;75:388-394. 34. Wijdicks EF. Induced hypothermia in neurocatastrophes: feeling the chill. Rev Neurol Dis. 2004;1:10-15. 35. Wagner KR, Zuccarello M. Local brain hypothermia for neuroprotection in stroke treatment and aneurysm repair. Neurol Res. 2005;27:238-245.
Questions About ICH 1. Which one of the following most closely approximates the incidence of ICH? a. 37,000 cases per year b. 25,000 cases per year c. 11,000 cases per year d. 85,000 cases per year e. 50,000 cases per year 2. Which one of the following most closely represents the percentage of patients with ICH who are actively bleeding when they present to the ED? a. 10% b. 30% c. 5% d. 50% e. 1% 3. Which one of the following is the most accurate predictor of outcome in patients who have ICH? a. Hematoma volume b. Rate of hematoma growth c. Neurologic examination on presentation d. Time from onset to presentation e. INR at presentation 4. In which one of the following ways does hypothermia benefit patients with ICH? a. Induces shivering b. Produces bradycardia c. Stimulates the clotting cascade d. Protects the blood-brain barrier e. Maintains sedation 5. Which one of the following is the most likely cause of secondary cellular injury in ICH? a. Ischemia b. Inflammation c. Low blood pressure d. Edema e. Toxins
Correct answers: 1. a, 2. b, 3. a, 4. d, 5. b
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