Neurol Sci (2008) 29:S271S273 DOI 10.

1007/s10072-008-0961-y

ANNUAL MEETING OF SIN/SNO LOMBARDIA

Intracerebral hemorrhage: medical treatment

Paola Santalucia

Springer-Verlag 2008

Abstract Intracerebral hemorrhage (ICH) accounts for between 10% to 30% of first-ever strokes; outcomes are significantly worse than with ischemic stroke with a 30-day mortality rate up to 50%, furthermore, half of the deaths occur in the acute phase. Intracerebral hemorrhage (ICH) is classified as primary or secondary according to the underlying etiology. Primary ICH (about 80%) comes from the spontaneous rupture of small vessels more often in relation to long-standing or uncontrolled arterial hypertension and is generally located in the basal ganglia and internal capsula. Secondary ICH (about 20%) is often associated with vascular abnormalities, tumors, and anticoagulant therapy or coagulation disorders, more frequently located in cerebral lobes or subtentorial (cerebellum or pons). Rapid recognition and diagnosis of ICH as well as identification of early prognostic indicators are essential for planning the level of care and avoiding acute rapid progression during the first hours. Hematoma size has been identified as one of the most important predictors of 30-day mortality and its expansion is highly pre-

dictive of neurological deterioration [1]. Blood pressure management remains, although controversial, the firstline medical approach along with possible new and effective treatments coming from the numerous between pilot and larger randomized medical trials for ICH completed in the past decade. Keywords Intracerebral hemorrhage Medical management

Medical treatment of acute ICH General treatment of ICH includes an overall supportive medical approach through the management of airways and ventilatory measures, circulation stabilization, fever and glucose level control, nutrition as well as prophylaxis for seizure and deep vein thrombosis [2]. A standardized medical approach begins with simple measures, such as head positioning [head elevation to 30 improves jugular venous outflow and lowers intracranial pressure (ICP)] and appropriate sedation to more aggressive clinical strategies as indicated. Increase of ICP and consequent possible mass effect result in neurological deterioration. Specific treatments for increased ICP secondary to head trauma may not necessarily apply to ICH patients; cerebral perfusion pressure (CPP) should be kept as much as possible >70 mmHg where ICP is monitored. Hyperventilation is one of the most effective method available for rapid reduction of ICP through the physiological mechanism of cerebral blood flow (CBF) regulation. However its use is limited due to its transient effect and its simultaneous lowering of PCO2 level and CBF. Osmotic therapy, despite little evidence of its efficacy, is commonly used in patients with large ICH and increased ICP; the agent most often used is mannitol,

Paola Santalucia () Istituto Auxologico Italiano, IRCCS U.O. Cardiologia Ospedale San Luca Via Spagnoletto 3, 20149 Milano, Italy e-mail: santalucia@auxologico.it

S272

Neurol Sci (2008) 29:S271S273

which acts as an intravascular osmotic agent thus decreasing ICP through cerebral autoregulation; its use should however be limited to a few days mostly due to electrolyte imbalance and renal function alteration. Invasive monitoring of ICP with intraventricular catheter positioning, in selected critical cases, allows CSF drainage that in turn is effective for lowering ICP especially in case of hydrocephalus. Acute blood pressure management and treatment remain controversial and the association of a hypertensive status to hematoma enlargement is unclear. Persistent marked elevation of blood pressure can predispose to hematoma expansion; however, it may also represent a protective response to preserve cerebral perfusion mainly in the areas of focal ischemia around the hematoma where reduction of blood pressure could promote further ischemia. It is, therefore, difficult to indicate what is the limit for aggressive blood pressure treatment. An acceptable target blood pressure value should be tailored on the individual patients factors such as history of hypertension and baseline blood pressure, age, and the presumed cause of bleeding, as well as correlated with intracranial pressure. The main goal for lowering blood pressure is avoiding hematoma enlargement; this is especially true for bleeding resulting from a ruptured aneurysm or arteriovenous malformation. However, in primary ICH, in which a specific large vessel rupture is not evident, the risk of hematoma enlargement that is blood pressure related may be lower and must be balanced with the theoretical risks of inducing cerebral ischemia in the area surrounding the hematoma. Despite the weak evidence to support a specific blood pressure threshold, the recommendation from the AHA/ASA Guidelines is to maintain a systolic blood pressure <180 mmHg and/or mean arterial pressure <130 mmHg [3]. Suggested medications for treatment of high blood pressure in the acute setting of ICH include labetalol, nicardipine, esmolol, enalapril, hydralazine, and nitroglycerin [3]. Recent pilot trials of acute blood pressure management, the Antihypertensive Treatment of Acute Cerebral Haemorrhage (ATACH) trial and the Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage trial (INTERACT), have been designed to determine the tolerability and the safety of different targeted acute blood pressure treatments in patients with ICH [4]. Preliminary results favor pharmacological aggressive reduction of systolic blood pressure (SBP 140 mmHg) in patients with acute ICH compared to less intensive treatment based on AHA guidelines, in terms of reducing hematoma growth in the acute phase of bleeding and offering better chances of recovery. The observation that early hematoma growth is a dynamic process due to ongoing bleeding and rebleeding

over several hours during the acute phase of ICH and its correlation to neurological deterioration represents the rationale for intervention with ultra-early hemostatic therapy. Recombinant activated factor VII (rFVIIa) is an approved treatment for bleeding disorders in patients with hemophilia who present antibodies to factor VIII or IX and has been reported to reduce bleeding in patients without coagulopathy as well; its application in the ICH setting has been tested in two small dose-ranging pilot safety studies and in two larger dose-finding phase II and III randomized trials [57]. Results from the phase II trial show that treatment with rFVIIa within 4 h after ICH onset limited the growth of the hematoma, reduced the mortality rate, and improved functional outcome at 90 days despite a small increase in the frequency of thromboembolic adverse events. The results of the phase III trial, although consistent with the previous one in terms of dose-related hematoma growth reduction and safety profile, showed no statistical difference in the trials primary endpoint (mortality and severe disability) between the treated and control groups.

Conclusions Intracerebral hemorrhage (ICH) causes 10%15% of first-ever strokes with a 30-day mortality rate between 35% to 52%, with half of the deaths occurring within 48 h from the onset. Identification of prognostic indicators during the first hours is crucial and important for planning the level of care and applying the appropriate treatment. Recent investigations on acute blood pressure management indicate that early intensive BP lowering reduces hematoma growth in ICH without increasing the risks of serious adverse events or a poor outcome; however, larger randomized trials are needed. Disappointing results from a phase III rFVIIa trial suggest the need for a better definition of the target population to identify an optimal responder group. The prognosis of ICH remains frequently poor despite the best medical management; however, the recent increase in clinical trials for ICH management provides hope for new and effective treatments.

Conflict of Interest statement The Authors declare that they have no conflict of interest related to the publication of this manuscript

References
1. Broderick J, Brott TG, Duldner JE et al (1993) Volume of intracerebral hemorrhage: a powerful and easy-to-use predictor of 30day mortality. Stroke 24:987993

Neurol Sci (2008) 29:S271S273 2. Neeraj SN, Nyquisit PA, Carhuapoma JR (2007) Advances in the management of spontaneous intracerebral hemorrhage. Crit Care Clin 607617 3. Broderick J, Connolly S, Feldmann E et al (2007) Guidelines for the management of spontaneous intracerebral hemorrhage in adults. 2007 Update. Stroke 38:20012023 4. Qureshi AI (2007) Antihypertensive treatment of acute cerebral hemorrhage (ATACH). Neurocrit Care 06:5666

S273 5. Mayer SA, Brun NC, Broderick J et al (2005) Safety and feasibility of recombinant factor VIIa for acute intracerebral hemorrhage. Stroke 36:7479 6. Mayer S, Brun NC, Begtrup K et al (2005) Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 352:777785 7. Mayer S (2007) Recombinant activated factor VII for acute intracerebral hemorrhage. Stroke 38:763767