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Advances in the Care of Patients With Intracerebral Hemorrhage

2007; Elsevier BV; Volume: 82; Issue: 8 Linguagem: Inglês

10.4065/82.8.987

1942-5546

Kristine M. Thompson, Sharon Y. Gerlach, H. Jörn, Jan M. Larson, Thomas G. Brott, Julia A. Files,

Neurosurgical Procedures and Complications

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. 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. Intracerebral 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,1Broderick JP Adams Jr, HP 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: 905-915Crossref PubMed Scopus (776) Google Scholar comprising 15% to 30% of all strokes. Intracerebral hemorrhage is the most lethal type of stroke, with an overall mortality of 40% to 50%.2Frankowski RF Epidemiology of stroke and intracerebral hemorrhage.in: Kaufman HH Intracerebral Hematomas. Raven Press, New York, NY1992: 1-11Google Scholar 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. 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 al3Broderick 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: 987-993Crossref PubMed Scopus (1411) Google Scholar demonstrated that hematoma volume was the most accurate predictor of outcome (Figure 1). Using serial computed tomographic scans, Brott et al4Brott T Broderick J Kothari R et al.Early hemorrhage growth in patients with intracerebral hemorrhage.Stroke. 1997; 28: 1-5Crossref PubMed Scopus (1168) Google Scholar documented that up to 30% of patients are actively bleeding when they present to the ED. Furthermore, hematoma growth has been found to be an independent determinant of both mortality and functional outcome.5Davis SM Broderick J Hennerici M Recombinant Activated Factor VII Intracerebral Hemorrhage Trial Investigators et al.Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage.Neurology. 2006; 66: 1175-1181Crossref PubMed Scopus (855) Google Scholar Between 8% and 14% of all ICHs occur in patients receiving anticoagulant therapy, and these patients have a higher rate of rapid clinical deterioration.6Sjoblom L Hardemark HG Lindgren A et al.Management and prognostic features of intracerebral hemorrhage during anticoagulant therapy: a Swedish multicenter study.Stroke. 2001; 32: 2567-2574Crossref PubMed Scopus (186) Google Scholar 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.7Makris 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: 477-480PubMed Google Scholar Experts recommend concomitant administration of vitamin K. Thrombotic events have been reported with PCC infusion.8Aguilar 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: 82-92PubMed Scopus (249) Google Scholar 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, raising the possibility of its usefulness in other devastating forms of hemorrhage.9Martinowitz U Kenet G Segal E et al.Recombinant activated factor VII for adjunctive hemorrhage control in trauma.J Trauma. 2001; 51: 431-438Crossref PubMed Scopus (427) Google Scholar It has a half-life of 2.3 hours,10NovoSeven [package insert]. Novo Nordisk, Inc, Princeton, NJ2006Google Scholar effectively reverses an elevated INR, and accelerates coagulation in patients with normal ratios.11Freeman 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: 1495-1500Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar, 12Mayer SA Brun NC Begtrup K Recombinant Activated Factor VII Intracerebral Hemorrhage Trial Investigators et al.Recombinant activated factor VII for acute intracerebral hemorrhage.N Engl J Med. 2005; 352: 777-785Crossref PubMed Scopus (1152) Google Scholar Freeman et al11Freeman 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: 1495-1500Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar 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 al12Mayer SA Brun NC Begtrup K Recombinant Activated Factor VII Intracerebral Hemorrhage Trial Investigators et al.Recombinant activated factor VII for acute intracerebral hemorrhage.N Engl J Med. 2005; 352: 777-785Crossref PubMed Scopus (1152) Google Scholar 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 coagulopathy 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.13Novo Nordisk A/S Stock exchange announcement no. 5/2007. February 26, 2007.Available at: www.novonordisk.com/investors/sea/sea.asp?sShowNewsItemGuID=0cfc120c-f013-4ad6-9130-55227465e3e8&sShowLanguageCode=en-GB&sSearchText=Cardiac+surgeryGoogle Scholar 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.14Nath FP Jenkins A Mendelow AD Graham DI Teasdale GM Early hemodynamic changes in experimental intracerebral hemorrhage.J Neurosurg. 1986; 65: 697-703Crossref PubMed Scopus (116) Google Scholar, 15Bullock 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: 101-107Abstract Full Text PDF PubMed Scopus (93) Google Scholar 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 al16Powers WJ Zazulia AR Videen TO et al.Autoregulation of cerebral blood flow surrounding acute (6 to 22 hours) intracerebral hemorrhage.Neurology. 2001; 57: 18-24Crossref PubMed Scopus (288) Google Scholar 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.17Qureshi AI Tuhrim S Broderick JP Batjer HH Hondo H Hanley DF Spontaneous intracerebral hemorrhage.N Engl J Med. 2001; 344: 1450-1460Crossref PubMed Scopus (1322) Google Scholar 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.18Bauer RB Tellez H Dexamethasone as treatment in cerebrovascular disease, 2: a controlled study in acute cerebral infarction.Stroke. 1973; 4: 547-555Crossref PubMed Scopus (90) Google Scholar, 19Norris JW Steroid therapy in acute cerebral infarction.Arch Neurol. 1976; 33: 69-71Crossref PubMed Scopus (95) Google Scholar, 20Dyken M White PT Evaluation of cortisone in the treatment of cerebral infarction.JAMA. 1956; : 1531-1534Crossref Scopus (44) Google Scholar, 21Mulley G Wilcox RG Mitchell JR Dexamethasone in acute stroke.Br Med J. 1978; 2: 994-996Crossref PubMed Scopus (77) Google Scholar, 22Norris JW Hachinski VC High dose steroid treatment in cerebral infarction.Br Med J (Clin Res Ed). 1986; 292: 21-23Crossref PubMed Scopus (139) Google Scholar 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.23Poungvarin N Bhoopat W Viriyavejakul A et al.Effects of dexamethasone in primary supratentorial intracerebral hemorrhage.N Engl J Med. 1987; 316: 1229-1233Crossref PubMed Scopus (279) Google Scholar 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.24Feigin 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; (CD004583)Google Scholar 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 increased 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.25Rasool AH Rahman AR Choudhury SR Singh RB Blood pressure in acute intracerebral haemorrhage.J Hum Hypertens. 2004; 18: 187-192Crossref PubMed Scopus (30) Google Scholar These findings are consistent with the American Heart Association recommendation to maintain mean arterial pressure below 130 mm Hg in patients with acute ICH.1Broderick JP Adams Jr, HP 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: 905-915Crossref PubMed Scopus (776) Google Scholar 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 al26Morgenstern LB Frankowski RF Shedden P Pasteur W Grotta JC Surgical treatment for intracerebral hemorrhage (STICH): a single-center, randomized clinical trial.Neurology. 1998; 51: 1359-1363Crossref PubMed Scopus (261) Google Scholar and Zuccarello et al,27Zuccarello M Brott T Derex L et al.Early surgical treatment for supratentorial intracerebral hemorrhage: a randomized feasibility study.Stroke. 1999; 30: 1833-1839Crossref PubMed Scopus (265) Google Scholar 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.28Mendelow AD Gregson BA Fernandes HM STICH Investigators et al.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: 387-397Abstract Full Text Full Text PDF PubMed Scopus (1037) Google Scholar The STICH authors28Mendelow AD Gregson BA Fernandes HM STICH Investigators et al.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: 387-397Abstract Full Text Full Text PDF PubMed Scopus (1037) Google Scholar 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.29Wagner KR Dwyer BE Hematoma removal, heme, and heme oxygenase following hemorrhagic stroke.Ann N Y Acad Sci. 2004; 1012: 237-251Crossref PubMed Scopus (39) Google Scholar 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 study30Qureshi 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: 1556-1564Crossref PubMed Scopus (95) Google Scholar 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 the use of induced hypothermia as a neuroprotective agent in acute stroke.31Bernard 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: 557-563Crossref PubMed Scopus (4241) Google Scholar, 32Hypothermia 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: 549-556Crossref PubMed Scopus (4462) Google Scholar The use of hypothermia for treatment of ICH was reported as early as 1956.33Howell DA Posnikoff J Stratford JG Prolonged hypothermia in treatment of massive cerebral haemorrhage: a preliminary report.Can Med Assoc J. 1956; 75: 388-394PubMed Google Scholar 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 surface-cooling techniques, including infectious complications, clotting abnormalities, cardiac arrhythmias, and difficulty in rapidly achieving target temperatures.34Wijdicks EF Induced hypothermia in neurocatastrophes: feeling the chill.Rev Neurol Dis. 2004; 1: 10-15PubMed Google Scholar 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.35Wagner KR Zuccarello M Local brain hypothermia for neuroprotection in stroke treatment and aneurysm repair.Neurol Res. 2005; 27: 238-245Crossref PubMed Scopus (52) Google Scholar 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. 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.