Management of ICH, Part II

October 1, 2006

The prognosis for patients with intracerebral hemorrhage (ICH) is poor. The 30-day mortality rate is 25% to 50%, and half of these deaths occur within the first 48 hours.

The prognosis for patients with intracerebral hemorrhage (ICH) is poor. The 30-day mortality rate is 25% to 50%, and half of these deaths occur within the first 48 hours.1 Patients should be admitted to an acute stroke unit or ICU. Those admitted to a specialized neurologic unit have improved outcomes relative to those admitted to a general ICU.2 Older age, impaired level of consciousness on admission, elevated blood pressure (BP) on admission, and inhospital neurologic deterioration are predictive of poor outcome.

Treatment strategies for ICH focus on medical stabilization, prevention or amelioration of secondary injury, and supportive care. Acute treatment begins with management of airway, respiration, and hemodynamic status. Only 1 intervention has shown benefit in improving clinical outcome after ICH: administration of recombinant activated factor VIIa (rFVIIa) within 4 hours of symptom onset.

MEDICAL STABILIZATIONAirway and respiratory management. Diminished consciousness may cause airway obstruction because the pharyngeal muscles relax and cough and gag reflexes are suppressed. In addition, hemorrhage in or compression of the brain stem may directly suppress cough and gag reflexes. Initial airway management includes proper positioning, frequent suctioning, placement of an oral or nasal airway, and repeated assessments for evidence of respiratory compromise. As many as half of all patients with ICH require mechanical ventilation.3 Preventing a rise in intracranial pressure (ICP) during intubation and taking appropriate measures to minimize the risk of pneumonia are areas of special concern in mechanically ventilated ICH patients.

BP management. Management of BP in ICH is highly controversial. Guidelines for BP management in ICH provided by the American Heart Association (AHA) Stroke Council suggest acutely lowering BP when mean arterial pressure (MAP) is 130 mm Hg or greater,4 but this recommendation is based on nonrandomized retrospective trials and anecdotal reports.

The rationale for the treatment of acute hypertension is multifaceted but not entirely supported by data. Those who advocate prompt treatment frequently maintain that high BP predisposes to hematoma expansion and may exacerbate vasogenic edema by increasing capillary hydrostatic pressure, especially in areas with a damaged blood-brain barrier. In fact, data on the effect of hypertension on hematoma enlargement are inconsistent,5-7 and an association between hypertension and edema has never been demonstrated.

Another reason to treat hypertension in acute ICH is that elevated admission BP may correlate with a poor prognosis.8 Causality has not been established, however, so it does not necessarily follow that lowering BP will improve outcome. In one study, patients in whom MAP could be lowered to less than 125 mm Hg had a better outcome,9 but whether lowering the BP improved outcome or whether patients who respond to antihypertensive medications have less severe injury is unclear. Other studies have found no relationship between BP at hospital admission and mortality.10 A final consideration favoring treatment of elevated BP in ICH is the potential for moderate to severe hypertension to produce acute systemic complications, including myocardial ischemia, congestive heart failure, and acute renal failure.

Conversely, the major argument against the treatment of acute hypertension is that lowering BP may impair blood flow, exacerbating ischemic damage in the tissue surrounding the hematoma.11 Chronic hypertension shifts the cerebral autoregulatory curve to the right such that a higher cerebral perfusion pressure (CPP) is required to maintain adequate cerebral blood flow.12 Treating hypertension acutely might reduce CPP below the autoregulatory limit, leading to inadequate cerebral blood flow and subsequent ischemia, especially in patients in whom ICP is elevated because of a large space-occupying hematoma or hydrocephalus.

Several studies of cerebral blood-flow autoregulation in patients with recent ICH and elevated BP (MAP greater than 130 to 140 mm Hg) have addressed the issue of whether lowering BP produces cerebral ischemia.13-15 Overall, these studies demonstrate that after ICH, autoregulation is preserved globally as well as locally around the hematoma down to a lower MAP limit of approximately 110 mm Hg, or about 20% of the admission MAP. Reductions in excess of 20% or below approximately 85 mm Hg may reduce cerebral blood flow. Because the studies involved patients with small or moderate-size hematomas (or hematoma size not specified) and did not provide ICP data, it is not known whether autoregulation is intact in patients with large hematomas or elevated ICP (Figure 1).

To summarize, there appears to be no compelling reason to aggressively treat hypertension in acute ICH in the absence of systemic complications of elevated BP, especially in the setting of large hematomas or elevated ICP. On the other hand, when treatment is deemed to be necessary in markedly hypertensive patients (MAP more than 130 to 140 mm Hg) with small to moderate-size hemorrhages, modest reductions (15% to 20%) in BP appear to be safe. In these cases, rational selection of an antihypertensive agent that has a short half-life and minimal cerebrovascular effects and is administered via a dose and route that avoids sudden large reductions in BP is optimal. The most popular agents used in this setting are the combined α- and ß-blocker labetalol, the calcium channel blocker nicardipine, and the angiotensin-converting enzyme inhibitor enalapril.

PREVENTION OF SECONDARY INJURYPrevention of hematoma enlargement. Because hematoma volume and early hematoma growth are powerful determinants of poor outcome after ICH, the phase 2 double-blind placebo-controlled Recombinant Activated Factor VII Intracerebral Hemorrhage Trial16 was undertaken in 2002 to determine whether ultra-early hemostatic therapy with rFVIIa might reduce hematoma growth, thus improving outcome. rVIIa is the physiologic initiator of coagulation and works in the coagulation cascade to accelerate and strengthen local hemostasis.

In this trial, 399 patients were randomly assigned to receive a single intravenous dose of rFVIIa 40, 80, or 160 µg/kg or placebo. Treatment was given within 1 hour after the baseline CT and no later than 4 hours after the onset of symptoms. There was a dose-dependent effect of rFVIIa on the primary end point of hematoma growth. The mean increase in hematoma size was 16%, 14%, and 11% in the 40, 80, and 160 µg/kg rFVIIa groups, respectively, compared with 29% in the placebo group (P = .01). Fewer rFVIIa-treated patients died (18% vs 29%; P = .02), and more achieved a good outcome, but arterial thromboembolic events (myocardial ischemia or cerebral infarction) occurred more frequently in patients treated with rFVIIa than in patients treated with placebo, particularly in those patients receiving the highest dose. The phase 3 Recombinant Factor VIIa in Acute Intracerebral Haemorrhage Trial (FAST) testing doses of 20 and 80 µg/kg versus placebo is ongoing.

Correction of coagulopathy: oral anticoagulant (OAC)-associated ICH. Patients taking OACs were excluded from the Recombinant Activated Factor VII Intracerebral Hemorrhage Trial and the ongoing FAST study, so no data are available to guide hemostatic therapy in this population. But because OAC use is associated with an increased risk of hematoma enlargement and because the length of time of risk is 2.5 times longer than it is for non-anticoagulated patients,17 it seems appropriate that the coagulopathy should be corrected rapidly and the treatment response sustained for as long as 24 hours.

Treatment options for reversing the effects of OAC therapy include:

  • Vitamin K, which has a slow onset but has long duration of action and therefore is useful in achieving sustained reversal of OAC effects.
  • Fresh frozen plasma (FFP), which contains all the coagulation factors in a nonconcentrated form and is effective within about 45 to 60 minutes but requires a large volume (up to several liters) and thus may lead to circulatory overload.
  • Prothrombin complex concentrate (PCC), which is a concentrated form of clotting factors II, IX, and X, with or without small amounts of clotting factor VII and corrects the international normalized ratio 4 to 5 times faster than does FFP: within 10 minutes of administration. PCC may be thrombogenic and does not have FDA approval for this indication, however.orFVIIa.

Thrombolysis-associated ICH. Symptomatic ICH occurs after thrombolytic treatment of acute ischemic stroke in 3% to 21% of patients.18-20 It is substantially less common after thrombolytic treatment of extracerebral thrombosis21 but results in a similarly poor outcome.22 Management of thrombolysis-associated ICH begins with stopping the thrombolytic infusion; evaluating the patient's airway; and assessing fibrinolytic state with measurement of prothrombin time, partial thromboplastin time, thrombin, and fibrinogen levels. Treatment options include FFP, cryoprecipitate, and/or platelets. The National Institute of Neurological Disorders and Stroke rt-PA study18 stipulated 6 to 8 units of cryoprecipitate or FFP and 6 to 8 units of platelets, but only rarely was this amount of blood product given to an individual patient during the study.

Management of intraventricular hemorrhage (IVH) and hydrocephalus. Extension of blood into the ventricular system complicates ICH in about 40% of patients and is associated with a poor prognosis.23 The 2 possible mechanisms by which IVH may contribute to poor outcome are (1) blocking cerebrospinal fluid pathways, resulting in hydrocephalus and increased ICP; and (2) direct chemical irritation of periventricular structures.

Hydrocephalus may complicate ICH in the setting of either IVH
or external compression of the ventricular system by the hematoma (Figure 2). Although external ventricular drainage (ventriculostomy) is often used to treat hydrocephalus and IVH, its effectiveness has yet to be shown. A retrospective series suggests that it does not improve outcome.24 The presence of IVH complicates ventriculostomy management because a thrombus often obstructs the catheter. Although flushing the system may remove the thrombus, this approach increases the risk of ventriculitis.

A potential role for direct intraventricular thrombolytic administration in facilitating removal of IVH was recently evaluated in a pilot study.25 Instillation of urokinase, which is no longer available in the United States, was associated with a trend toward reduced mortality and no increase in complications. A multicenter randomized study of intraventricular tissue plasminogen activator is under way.

Management of intracranial hypertension. ICP can be monitored by a device placed in an extradural, subdural, intraparenchymal, intraventricular, or intraspinal location. Although the AHA Stroke Council recommends ICP monitoring in patients with a Glasgow Coma Scale score of less than 9 or in whom deterioration is thought to be secondary to elevated ICP, there is no evidence that such monitoring alters outcome or is useful in prognostication.23

Because monitoring is not routinely performed, the incidence of intracranial hypertension in ICH is unknown. In addition, such monitoring is likely to underestimate the incidence because hematomas may produce only a local increase in pressure that is partially offset by a reduction in the size of the ventricles and the subarachnoid space. A global increase in ICP only may be seen when the hematoma is massive or is associated with marked hydrocephalus. Of importance, local tissue shifts can result in brain stem compression and herniation in the absence of a global increase in ICP.26

The appropriate management of intracranial hypertension in ICH is also not known. If ICP is elevated or there are signs of herniation, initial treatment measures include elevation of the head of the patient's bed and hyperventilation. Osmotic agents (mannitol, hypertonic saline) or diuretics can be given, and if hydrocephalus is present, cerebrospinal fluid can be drained via ventriculostomy.

Although rapid reversal of clinical transtentorial herniation (defined by decreased consciousness and dilated pupil) with hyperventilation and osmotic therapy was associated with improved long-term outcome in one case series,27 no randomized controlled trial data exist to guide the use of these agents. Such data do exist for corticosteroids, which have been demonstrated to provide no benefit and increase the rate of medical complications in ICH.28

Surgical evacuation. Surgical hematoma evacuation has been studied for nearly half a century as a means of achieving hemostasis, reducing mass effect, and removing toxic clot constituents to minimize brain injury and ultimately improve outcome. In total, 9 randomized controlled trials of surgery for supratentorial ICH29-37 and 3 meta-analyses38-40 have been published, yielding nearly uniformly disappointing results. Yet proponents of surgery continue to pursue the question of its potential benefit.

The early trials were criticized for outdated surgical techniques, inadequate patient selection, and unacceptable delay of surgery. A variety of newer techniques for clot removal were proposed that circumvented the tissue damage incurred with open craniotomy, but they did not eliminate the risk of re-bleeding due to the loss of tamponade effect on adjacent tissue. In addition, the newer techniques involve limited surgical exposure, raising concern of how well this re-bleeding might be controlled. The more recent studies33,35-38,41 have focused on shortening the time to surgery. Despite achieving this goal, no clinical benefit for surgery was seen. In fact, the 1 uncontrolled study of ultra-early surgery (at less than 4 hours from the hemorrhagic event) found a disturbingly high rate of postoperative re-bleeding.41

The results of the long-awaited International Surgical Trial in Intracerebral Haemorrhage (STICH)34 were published in 2005 and were expected to provide the definitive answer to the decades-old question of the efficacy of surgery in ICH. More than 1000 patients with supratentorial hemorrhage from 27 countries were randomized to early surgery or initial conservative treatment. Only 26% in the early surgery group and 24% in the initial conservative treatment group had a favorable outcome (defined as good recovery or moderate disability on the Glasgow Outcome Scale), thus confirming the lack of benefit of early surgery. However, the value of these results has been challenged because "early" surgery did not occur until a median of 30 hours after ictus, and 26% of patients randomized to initial conservative treatment crossed over and underwent surgery within a few days of study randomization. Therefore, less invasive methods for surgical hematoma evacuation at earlier times continue to be investigated.

Hemorrhage in the cerebellum has traditionally been considered an indication for surgery because of its perceived high morbidity and mortality42 and the relative ease of the surgical approach. Many patients with cerebellar hemorrhage have a benign outcome when managed medically, however.43 Various criteria have been proposed for when to evacuate a cerebellar hematoma (eg, diminished level of consciousness, hematoma size greater than 3 cm3, brain stem and/or basal cistern compression, and presence of hydrocephalus),44,45 but whether these criteria identify patients who will benefit from surgery has not been addressed in a randomized trial.

Management of seizures. Although seizures may theoretically exacerbate ICH, they have not been demonstrated to alter outcome,46 nor has the use of prophylactic anticonvulsants been shown to affect the risk of developing epilepsy. The recommendation by the AHA Stroke Council of 1 month of prophylactic phenytoin therapy is based on anecdotal evidence only.47 It is no less reasonable to treat only if seizures occur.

SUPPORTIVE CARE
ICH patients are prone to the same medical complications seen in ischemic stroke patients, including fever, deep venous thrombosis (DVT), pulmonary embolism, and pneumonia.47,48 The use of pneumatic sequential compression devices and elastic stockings has been shown to significantly decrease the incidence of DVT in patients with acute ICH relative to elastic stockings alone.49 Subcutaneous heparin at a dose of 5000 U tid when started on day 2 after hemorrhage has been shown to significantly reduce the frequency of DVT compared with treatment begun on day 4 or 10, with no concomitant increase in hematoma expansion.50

Similar to patients with ischemic stroke, ICH patients should not be fed orally until swallowing is evaluated. If aspiration is detected or the patient is not alert enough to eat safely, nasogastric tube feeding should be started promptly. Patients should be monitored for signs of aspiration pneumonia, whether taking food orally or via nasogastric tube.

As with ischemic stroke, prevention through risk factor management remains the most effective way to reduce mortality and morbidity caused by ICH.

Editor's Note: This work was supported by grants from the National Institutes of Health (NS35966 and 1K23NS044885).

REFERENCES1. Counsell C, Boonyakarnkul S, Dennis M, et al. Primary intracerebral haemorrhage in Oxford community stroke project 2. Prog Cerebrovasc Dis. 1995;5:26-34.
2. Diringer MN, Edwards DF. Admission to a neurologic/neurosurgical intensive care unit is associated with reduced mortality rate after intracerebral hemorrhage. Crit Care Med. 2001;29:635- 640.
3. Gujjar AR, Deibert E, Manno EM, et al. Mechanical ventilation for ischemic stroke and intracerebral hemorrhage: indications, timing, and outcome. Neurology. 1998;51:447-451.
4. 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.
5. Brott T, Broderick J, Kothari R, et al. Early hemorrhage growth in patients with intracerebral hemorrhage. Stroke. 1997;28:1-5.
6. Fujii Y, Tanaka R, Takeuchi S, et al. Hematoma enlargement in spontaneous intracerebral hemorrhage. J Neurosurg. 1994;80:51-57.
7. Maruishi M, Shima T, Okada Y, et al. Involvement of fluctuating high blood pressure in the enlargement of spontaneous intracerebral hematoma. Neurol Med Chir (Tokyo). 2001;41:300-304.
8. 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.
9. Dandapani BK, Suzuki S, Kelley RE, et al. Relation between blood pressure and outcome in intracerebral hemorrhage. Stroke. 1995;26:21-24.
10. Qureshi AI, Safdar K, Weil J, et al. Predictors of early deterioration and mortality in black Americans with spontaneous intracerebral hemorrhage. Stroke. 1995;26:1764-1767.
11. Powers WJ. Acute hypertension after stroke: the scientific basis for treatment decisions. Neurology. 1993;43:461-467.
12. Strandgaard S, Olesen J, Skinhoj E, Lassen NA. Autoregulation of brain circulation in severe arterial hypertension. Br Med J. 1973;1:507-510.
13. Kaneko T, Sawada T, Niimi T, et al. Lower limit of blood pressure in treatment of acute hypertensive intracerebral hemorrhage. J Cereb Blood Flow Metab. 1983;3:S51-S52.
14. von Helden A, Schneider GH, Unterberg A, Lanksch WR. Monitoring of jugular venous oxygen saturation in comatose patients with subarachnoid haemorrhage and intracerebral haematomas. Acta Neurochir Suppl (Wien). 1993;59:102-106.
15. Powers WJ, Zazulia AR, Videen TO, et al. Autoregulation of cerebral blood flow surrounding acute intracerebral hemorrhage. Neurology. 2001;57:18-24.
16. Mayer SA, Brun NC, Begtrup K, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med. 2005;352:777-785.
17. Flibotte JJ, Hagan N, O'Donnell J, et al. Warfarin, hematoma expansion, and outcome of intracerebral hemorrhage. Neurology. 2004;63:1059-1064.
18. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333:1581-1587.
19. Thrombolytic therapy with streptokinase in acute ischemic stroke. The Multicenter Acute Stroke Trial-Europe Study Group. N Engl J Med. 1996;335:145-150.
20. Albers GW, Bates VE, Clark WM, et al. Intravenous tissue-type plasminogen activator for treatment of acute stroke: the Standard Treatment with Alteplase to Reverse Stroke (STARS) study. JAMA. 2000;283:1145-1150.
21. Patel SC, Mody A. Cerebral hemorrhagic complications of thrombolytic therapy. Prog Cardiovasc Dis. 1999;42:217-233.
22. Mahaffey KW, Granger CB, Sloan MA, et al. Neurosurgical evacuation of intracranial hemorrhage after thrombolytic therapy for acute myocardial infarction: experience from the GUSTO-I trial. Global Utilization of Streptokinase and tissue-plasminogen activator (tPA) for Occluded Coronary Arteries. Am Heart J. 1999;138:493-499.
23. Portenoy RK, Lipton RB, Berger AR, et al. Intracerebral haemorrhage: a model for the prediction of outcome. J Neurol Neurosurg Psychiatry. 1987;50:976-979.
24. Adams RE, Diringer MN. Response to external ventricular drainage in spontaneous intracerebral hemorrhage with hydrocephalus. Neurology. 1998;50:519-523.
25. Naff NJ, Carhuapoma JR, Williams MA, et al. Treatment of intraventricular hemorrhage with urokinase: effects on 30-day survival. Stroke. 2000; 31:841-847.
26. Andrews BT, Chiles BW III, Olsen WL, Pitts LH. The effect of intracerebral hematoma location on the risk of brain-stem compression and on clinical outcome. J Neurosurg. 1988;69:518-522.
27. Qureshi AI, Geocadin RG, Suarez JI, Ulatowski JA. Long-term outcome after medical reversal of transtentorial herniation in patients with su-pratentorial mass lesions. Crit Care Med. 2000;28: 1556-1564.
28. Poungvarin N, Bhoopat W, Viriyavejakul A, et al. Effects of dexamethasone in primary supratentorial intracerebral hemorrhage. N Engl J Med. 1987;316:1229-1233.
29. McKissock W, Richardson A, Taylor J. Primary intracerebral hemorrhage: a controlled trial of surgical and conservative treatment in 180 unselected cases. Lancet. 1961;2:221-226.
30. Batjer HH, Reisch JS, Allen BC, et al. Failure of surgery to improve outcome in hypertensive putaminal hemorrhage. A prospective randomized trial. Arch Neurol. 1990;47:1103-1106.
31. Juvela S, Heiskanen O, Poranen A, et al. The treatment of spontaneous intracerebral hemorrhage. A prospective randomized trial of surgical and conservative treatment. J Neurosurg. 1989;70:755-758.
32. Auer LM, Deinsberger W, Niederkorn K, et al. Endoscopic surgery versus medical treatment for spontaneous intracerebral hematoma: a randomized study. J Neurosurg. 1989;70:530-535.
33. Teernstra OP, Evers SM, Lodder J, et al. Stereotactic treatment of intracerebral hematoma by means of a plasminogen activator: a multicenter randomized controlled trial (SICHPA). Stroke. 2003;34:968-974.
34. Mendelow AD, Gregson BA, Fernandes HM, 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;365:387-397.
35. Tan SH, Ng PY, Yeo TT, et al. Hypertensive basal ganglia hemorrhage: a prospective study comparing surgical and nonsurgical management. Surg Neurol. 2001;56:287-292.
36. Morgenstern LB, Frankowski RF, Shedden P, et al. Surgical treatment for intracerebral hemorrhage (STICH): a single-center, randomized clinical trial. Neurology. 1998;51:1359-1363.
37. Zuccarello M, Brott T, Derex L, et al. Early surgical treatment for supratentorial intracerebral hemorrhage: a randomized feasibility study. Stroke. 1999;30:1833-1839.
38. Hankey GJ, Hon C. Surgery for primary intracerebral hemorrhage: is it safe and effective? A systematic review of case series and randomized trials. Stroke. 1997;28:2126-2132.
39. Prasad K, Browman G, Srivastava A, Menon G. Surgery in primary supratentorial intracerebral hematoma: a meta-analysis of randomized trials. Acta Neurol Scand. 1997;95:103-110.
40. Fernandes HM, Gregson B, Siddique S, Mendelow AD. Surgery in intracerebral hemorrhage. The uncertainty continues. Stroke. 2000;31:2511-2516.
41. Morgenstern LB, Demchuk AM, Kim DH, et al. Rebleeding leads to poor outcome in ultra-early craniotomy for intracerebral hemorrhage. Neurology. 2001;56:1294-1299.
42. Ott KH, Kase CS, Ojemann RG, Mohr JP. Cerebellar hemorrhage: diagnosis and treatment. A review of 56 cases. Arch Neurol. 1974;31:160-167.
43. Dunne JW, Chakera T, Kermode S. Cerebellar haemorrhage-diagnosis and treatment: a study of 75 consecutive cases. Q J Med. 1987;64:739-754.
44. Kirollos RW, Tyagi AK, Ross SA, et al. Management of spontaneous cerebellar hematomas: a prospective treatment protocol. Neurosurgery. 2001;49:1378-1386.
45. Qureshi AI, Tuhrim S, Broderick JP, et al. Spontaneous intracerebral hemorrhage. N Engl J Med. 2001;344:1450-1460.
46. Kilpatrick CJ, Davis SM, Hopper JL, Rossiter SC. Early seizures after acute stroke. Risk of late seizures. Arch Neurol. 1992;49:509-511.
47. Zurasky JA, Aiyagari V, Zazulia AR, et al. Early mortality following spontaneous intracerebral hemorrhage. Neurology. 2005;64:725-727.
48. Bamford J, Dennis M, Sandercock P, et al. The frequency, causes and timing of death within 30 days of a first stroke: the Oxfordshire Community Stroke Project. J Neurol Neurosurg Psychiatry. 1990;53:824-829.
49. Lacut K, Bressollette L, Le Gal G, et al. Prevention of venous thrombosis in patients with acute intracerebral hemorrhage. Neurology. 2005;65:865-869.
50. Boeer A, Voth E, Henze T, Prange HW. Early heparin therapy in patients with spontaneous intracerebral haemorrhage. J Neurol Neurosurg Psychiatry. 1991;54:466-467.

Examples of evidenced-based medicine related to this article:

  • Counsell C, Boonyakarnkul S, Dennis M, et al. Primary intracerebral haemorrhage in the Oxford community stroke project 2. Prog Cerebrovasc Dis. 1995;5:26-34.
  • Mayer SA, Brun NC, Begtrup K, et al.Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med. 2005;352:777-785