Intracerebral hemorrhage (ICH) is an important cause of stroke-related death and disability.
Intracerebral hemorrhage accounts for ∼ 10 to 15% of all strokes in the United States
with an incidence of 12 to 15 cases per 100,000 per year.[1]
[2] The incidence is higher in Asian countries, at ∼ 20 to 30% of all strokes.[3] Mortality is almost 50% at 30 days, and half of these deaths occur within the first
24 hours.[1] Although no intervention tested in clinical trials to date has significantly demonstrated
improved functional outcome following ICH, recently completed and ongoing trials may
have a direct impact on the acute care of ICH patients. In this review, we discuss
acute management of ICH in light of recently completed and ongoing ICH clinical trials.
Prognosis in Intracerebral Hemorrhage
An important prognostic factor in ICH is the presenting hematoma volume and subsequent
hematoma expansion. Hematoma expansion occurs in upwards of 40% of ICH patients,[4]
[5] typically occurs within the first few hours, and portends neurologic deterioration,
poorer functional outcome, and increased mortality. Each 10% increase in hematoma
size from baseline has been associated with a 5% increase in mortality and 16% chance
of worse functional outcome.[6] Unfortunately, trials of hemostatic agents for ICH (discussed in more detail below)
have not shown improved functional outcomes.[7]
[8]
Concurrent intraventricular hemorrhage (IVH) is another factor that has been associated
with worse outcome after ICH. Intracerebral hemorrhage may lead to obstructive hydrocephalus
causing acute intracranial hypertension that may result in herniation syndromes. Mortality
rates of 50 to 80% have been reported in ICH patients with IVH.[9]
[10] Emergent placement of an extraventricular drain (EVD) may be life-saving and recent
studies suggest administration of recombinant tissue plasminogen activator (rt-PA)
or urokinase may facilitate resolution of the IVH.[11]
[12] A phase III clinical trial is ongoing to determine if resolution of IVH with rt-PA
is associated with improved long-term clinical outcome.
Other factors that have been associated with poorer outcome after ICH include age,
infratentorial ICH location, edema, and warfarin or other anticoagulant use. A variety
of prognostic tools have been published for ICH.[10]
[13] However, clinicians must be cautious regarding the so-called self-fulfilling prophecy
of ICH management,[14] whereby withdrawal of care or initiation of comfort care measures early in the clinical
course has become the leading proximate cause of death after ICH. This is particularly
important given recent data suggesting that functional outcomes after ICH continue
improve past the 6-month mark and reports of early morbidity and mortality may misrepresent
potential outcomes.[15]
Acute Management of Intracerebral Hemorrhage
Intracerebral hemorrhage is an emergency. The acute clinical presentation depends
on the location of the lesion within the brain. A sudden focal neurologic deficit,
change in consciousness, headache, or vomiting are common presentations. A computed
tomography (CT) scan or magnetic resonance imaging (MRI) is required to confirm a
diagnosis of ICH. Care should always begin with airway stabilization, breathing, and
circulation (ABCs). Specifically, many patients require active airway management with
endotracheal intubation and mechanical ventilation secondary to their depressed mental
status. The head of the bed should be elevated to 30 degrees at all times, and the
neck kept in a midline position. Adequate analgesia and sedation should be provided.
Other specific measures such as blood pressure management are crucial as well. Acute
emergency department (ED) interventions that can minimize bleeding are critical for
improved outcomes. These are discussed further below and in addition to the ABCs include
timely diagnosis, blood pressure management, and reversal of anticoagulation.
Imaging
Initial imaging and diagnosis of ICH is almost always made on a noncontrast head CT.
Addition of CT angiography (CTA) may reveal a “spot sign,” a hyperdensity within the
hematoma corresponding to contrast extravasation, which has been associated with subsequent
hematoma expansion.[16]
[17]
[18] In the largest prospective observational study published to date, 30% of 268 ICH
patients with ICH volume less than 100 mL who underwent CTA within 6 hours of symptom
onset had a spot sign.[18] Of these, 61% experienced hematoma expansion compared with 22% of patients who had
no spot sign. Sensitivity of the spot sign for predicting hematoma expansion was 51%
and specificity was 85%.[18]
Early CTA may also reveal secondary causes of ICH such as arteriovenous malformations
and aneurysms. Magnetic resonance imaging (MRI), MR angiography (MRA), catheter angiography
also play a significant role in identifying secondary causes of ICH and may be essential
prior to enrolling patients in clinical trials testing administration of rt-PA for
hastening clot resolution. The most recent American Stroke Association (ASA) guidelines
do not specify which ICH patients may benefit from vascular imaging for evaluation
of secondary causes.[1] However, recent clinical experience suggests such imaging may be warranted in more
patients than currently recognized, particularly in the young ([Fig. 1]).
Fig. 1 A 43-year-old woman with poorly controlled diabetes and hypertension who presented
with an intracerebral hemorrhage. A dural arteriovenous fistula is demonstrated on
computed tomography angiography.
Blood Pressure Control
Effective management of blood pressure, especially in the acute phase of ICH, is imperative.
The European Stroke Initiative (EUSI) in 2006 recommended that antihypertensive treatment
be initiated if systolic blood pressure (SBP) is ≥ 180 mm Hg,[19] which is similar to the ASA guidelines from 1999, which recommended treatment for
SBP ≥ 180 mm Hg or diastolic blood pressure (DBP) ≥ 105 mm Hg.[20] The 2007 ASA guidelines recommend treatment if SBP is ≥ 180 mm Hg or mean arterial
pressure (MAP) is ≥ 130 mm Hg and there is no evidence or suspicion of elevated ICP.
If there is concern for elevated ICP, then patients should have intracranial pressure
(ICP) monitoring, and cerebral perfusion pressure (CPP) should be maintained between
60 to 80 mm Hg.[21] In 2010, the ASA guidelines were further modified and recommended a goal SBP < 160 mm
Hg or a MAP below 110 mm Hg.[1] The guidelines further state that if SBP >180, or MAP >130 and increased ICP is
suspected, then ICP monitoring is recommended. Intravenous, short-acting medications
are recommended for treating acute hypertension in ICH. Recommended medications include
labetalol (5–20 mg every 15 minutes or infusion of 2 mg/min), nicardipine (infusion
of 5–15 mg/h), esmolol (bolus 250 μg/kg, infusion 25–300 μg/kg/min), enalaprilat (1.25–5 mg
every 6 hours with starting dose of 0.625 mg intravenously [IV]), hydralazine (5–10 mg
every 30 minutes, or infusion of 1.5–5 μg/kg/min), nitroprusside (infusion 0.1–10
μg/kg), or nitroglycerin (infusion 20–400 μg/min). In 2010, a goal SBP of 140 mm Hg
was considered “probably safe,” which was a modification from the 2007 guidelines.
The evolution of these practice guidelines reflects the growing evidence for blood
pressure management in ICH.
The pilot Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT)
trial evaluated 404 patients randomized to early BP lowering (systolic target 140 mm
Hg) versus standard management (target < 180 mm Hg) within 6 hours of onset.[22] Rapid blood pressure reduction following ICH was found to be safe in INTERACT. Further,
the intensive blood pressure control group demonstrated reduced hematoma expansion
(14% vs. 36%), but these results were not statistically significant.[22] Subsequently, ATACH and INTERACT2 were conducted and ATACH-2 is ongoing. Given the
current available evidence, we believe a target SBP of 140 mm Hg may be safe in the
early clinical (< 6 hours) course of acute ICH. It remains unclear whether the blood
pressure may be safely dropped to 140 mm Hg in the ultraearly period (< 3.5 hours)
and whether such early aggressive blood pressure control would result in improved
outcomes.
Hemostatics
Various hemostatic agents have been and are currently being tested as therapies for
the management of ICH. One hemostatic agent of high interest is recombinant activated
factor VII (rFVIIa). rFVIIa has been proven to significantly reduce hematoma expansion
in phase IIb (n = 339)[7] and phase III (n = 841)[8] trials when given within 4 hours of symptom onset. Unfortunately, clinical efficacy
in terms of improved outcomes was not demonstrated in those trials. A proposed explanation
for this lack of efficacy for improving outcomes despite reducing hematoma expansion
was the inclusion of an unselected patient population. Particularly, rFVIIa treatment
was associated with an ∼ 20% absolute increase in ischemic strokes and myocardial
infarction in the phase III trial.[23] Thus, exposure of patients who were not bound to experience hematoma expansion to
this risk may have blunted any benefits from reducing hematoma expansion in patients
who experienced expansion.[8] Patients with large hematomas were also included although they were bound to have
a poor outcome regardless of hematoma expansion. As such, it has been suggested that
patients aged 70 years or younger, ICH volume < 60 mL with minimal IVH and treated
within 2.5 hours may be a subset of patients who would benefit from rFVIIa.[24] Patient selection based on the spot sign may also select those patients most likely
to experience hematoma expansion.
Two ongoing trials are using early CTA to select ICH patients for treatment with rFVIIa.
The Spot Sign for Predicting & Treating ICH Growth (STOP-IT) study is an ongoing phase
II, randomized, multicenter, double-blind, placebo-controlled trial with the primary
goals of (1) determining the sensitivity and specificity of the CTA spot sign for
predicting hematoma expansion, (2) determining the feasibility of using CTA to identify
ICH patients at high risk of hematoma expansion and to select spot-positive patients
for randomization to treatment with rFVIIa or placebo, and (3) determining the rate
of hematoma expansion among spot-positive patients at 24 hours. The planned enrollment
is for 184 total patients.[25] The Spot Sign Selection of Intracerebral Hemorrhage to Guide Hemostatic Therapy
(SPOTLIGHT) study is also an ongoing, phase II, randomized, multicenter, double-blind,
placebo-controlled trial with similar goals of randomizing spot-positive ICH patients
to treatment with rFVIIa to those treated with placebo. The planned enrollment size
is 110 patients in Canada.[25]
Anticoagulant-Related Intracerebral Hemorrhage
About one in five cases of ICH are anticoagulant related.[26] Warfarin remains the most commonly used oral anticoagulant, and interventions that
reverse anticoagulation due to warfarin are crucial. Options for reversal of anticoagulation
due to warfarin include fresh frozen plasma (FFP), vitamin K, prothrombin complex
concentrates (PCCs), and rfVIIa, alone or in combination.[27]
Fresh frozen plasma and vitamin K remain the most commonly used reversal agents. Delays
in administration of FFP have been reported and every 30-minute delay in administration
of FFP is associated with a 20% reduction in successful INR correction by 24 hours
after presentation.[28] Vitamin K should be administered to all patients with warfarin-related ICH, but
it is not sufficiently effective in a short period to suffice as the only treatment
for ICH. Prothrombin complex concentrates may be classified as three factor (sufficient
levels of factors II, IX, and X, and low levels of factor VII) or four factor (sufficient
levels of factors II, VII, IX, and X, as well as proteins C and S). Prothrombin complex
concentrates are more effective than FFP in rapidly reversing anticoagulation due
to warfarin,[29] require less volume infusion, and can be delivered rapidly. As such, in addition
to vitamin K administration, four-factor PCCs is recommended over FFP for patients
with major bleeding.[27] Four-factor PCCs had been unavailable in the United States until the U.S. Food and
Drug Administration (FDA) approved Kcentra (CSL Behring GmbH, Marburg, Germany) in
May 2013. Given the life-threatening consequence of delays in reversal of anticoagulation
in patients with warfarin-related ICH, we believe four-factor PCCs should be first-line
therapy in addition to administration of vitamin K and additional FFP as needed.
Novel anticoagulant agents including direct thrombin inhibitors such as dabigatran
and factor Xa inhibitors such as rivaroxaban and apixaban have recently been approved
for treatment of atrial fibrillation and venous thromboembolism.[30]
[31]
[32]
[33] Although case vignettes of ICH and other major bleeding associated with these agents
have been published, no proven reversal regimens exist. As such, options for treating
ICH related to these novel anticoagulants are FFP, PPCs, and rFVIIa.
Surgical Management
Surgical management of ICH should be discussed in terms of approach (craniotomy/craniectomy
vs. minimally invasive approaches) and ICH location (supra- or infratentorial location).
Emergent craniectomy may be life-saving in patients with posterior fossa ICH, and
surgery is recommended in patients with posterior fossa hemorrhages larger than 3
cm in diameter, brainstem compression, or hydrocephalus from ventricular obstruction.[1] Because patients with posterior fossa lesions may regain close to full function
with this life-saving surgery, there is little controversy with this recommendation
and treatment approach. In the context of the STICH II results discussed below, it
remains unclear whether craniotomy/craniectomy is beneficial in supratentorial ICH.
Minimally invasive hematoma evacuation after ICH offers the benefit of removal of
offending factors in blood that may cause secondary injury without the morbidity associated
with craniotomy. The largest trial published to date randomized 377 patients with
small basal ganglia ICH (25–40 mL) to craniopuncture followed by urokinase and clot
aspiration versus medical therapy alone.[34] At 90 days, there was no significant difference in mortality (6.7% vs. 8.8%, p = 0.44), and the medical therapy group was more likely to be dependent (modified
Rankin score 3–6) (63% vs. 41%, p < 0.01).[34] The MISTIE III and CLEAR III trials will confirm whether this approach is associated
with improved long-term outcomes in treated patients.
Neuroprotective Strategies
In addition to direct tissue destruction and mass effect on adjacent tissues, ICH
may trigger many deleterious inflammatory cascades. These include tissue necrosis,
cellular apoptosis, and edema. Various neuroprotective approaches are being evaluated
for efficacy in reducing secondary injury after ICH. To our knowledge, none are currently
mature enough for phase III clinical trial evaluation.
Phase III Clinical Trials in Intracerebral Hemorrhage
Clinical Trials Published in 2013
Two critical phase III clinical trials of ICH were published in the past year: (1)
rapid blood-pressure lowering in patients with acute intracerebral hemorrhage (INTERACT2)[35] and (2) early surgery versus initial conservative treatment in patients with spontaneous
supratentorial lobar intracerebral hematomas (STICH II), a randomized trial.[36]
INTERACT2 randomized 2839 patients with spontaneous ICH diagnosed on CT or MRI who
presented within 6 hours to an intensive treatment to lower blood pressure (target
systolic of < 140 mm Hg within 1 hour) or current guideline-recommended treatment
(target systolic level of < 180 mm Hg). Patients were eligible if they had a systolic
blood pressure (SBP) between 150 and 220 mm Hg and had no contraindication to blood
pressure lowering. Antihypertensive medication choices were at the discretion of the
treating physician. Of 2,794 patients for whom the primary outcome of death or major
disability (defined as a score of 3–6 on the modified Rankin scale) was available
at 90 days, 52% in the intensive group versus 56% in the standard treatment group
had the primary outcome (odds ratio = 0.87; 95% CI = 0.75–1.01, p = 0.06). The authors concluded that intensive blood pressure reduction in acute ICH
was safe, but did not significantly reduce death or major disability.[35]
The STICH II trial hypothesized that early surgery could improve outcome in conscious
patients in whom there was a superficial ICH of 10 to 100 mL and no evidence of IVH.
STICH II randomized 601 patients from 78 centers in 27 countries to early surgery
(within 12 hours of ictus) or initial conservative treatment. The primary outcome
was a prognosis-based favorable or unfavorable outcome based on the Extended Glasgow
Outcome Scale (GOSE) at 6 months after randomization. Forty-one percent (123 out of
297) of patients in the early surgery group had a favorable outcome at 6 months compared
with 38% (108 out of 286) of patients in the initial conservative treatment group
(OR = 0.86, 95% CI = 0.62–1.20, p = 0·367). Notably, 21% of the initial conservative treatment group in STICH II had
surgery, thereby potentially blunting any treatment effect that may have been observed.
Ultimately, it remains unclear what subgroup of ICH patients would benefit from surgery
although ongoing studies may better define this.[36]
Ongoing Phase III ICH Clinical Trials
To our knowledge, there are three ongoing phase III acute interventional trials in
ICH. The Antihypertensive Treatment of Cerebral Hemorrhage (ATACH) 2 trial is randomizing
ICH patients to a goal SBP of < 140 mm Hg versus < 180 mm Hg within 3.5 hours of symptom
onset. Blood pressure targets are to be maintained for 24 hours after randomization.
Both arms of the trial receive nicardipine in standard dosing regimens established
per trial protocol.[37] Labetalol may also be used if maximum amounts of nicardipine are used. Given the
relatively delayed onset to initiation of therapy (< 6 hours), the multiple medications
used and the difference in time from randomization to initiation of antihypertensive
therapy between the treatment groups in INTERACT2,[35] ATACH 2 should provide further data on the safety and efficacy of ultraearly (<
3.5 hours) rapid reduction of blood pressure using a single antihypertensive agent
after ICH.
With a planned enrollment of 500 ICH patients with IVH, the Clot Lysis: Evaluating
Accelerated Resolution of Intraventricular Hemorrhage (CLEAR) III trial is randomizing
ICH patients who require an EVD for obstructive hydrocephalus due to third or fourth
ventricular blood to recombinant tissue plasminogen activator (rt-PA) versus placebo
for resolving the IVH. Treatment must begin within 72 hours of the diagnostic CT scan.
In addition to third or fourth ventricular obstruction, eligible patients must have < 30
mL of ICH. The primary outcome measure is the modified Rankin scale score at 180 days.[38]
The Minimally Invasive Surgery Plus Rt-PA for ICH Evacuation (MISTIE) Phase III trial
is a randomized clinical trial of minimally invasive surgery plus rt-PA versus medical
therapy alone after ICH. Eligible patients must have supratentorial ICH ≥ 30 mL, symptom
onset within 24 hours of diagnostic CT and initiation of treatment from 12 to 72 hours
of the diagnostic CT, with the first dose given within 76 hours of the diagnostic
CT. The primary efficacy outcome measure is a 12% increase in the proportion of rt-PA
treated patients with a modified Rankin score of 0 to 3 compared with medically treated
patients at 180 days. The primary safety outcome measure is the rate of mortality,
rebleeding, and infection at 30 days.[39]
These ongoing trials complement the recently completed trials and have a direct clinical
impact on the bedside management of ICH. [Table 1] summarizes recently completed and ongoing phase III clinical trials of ICH.
Table 1
Recently completed and ongoing phase III clinical trials of ICH
|
Trial
|
Number of trial participants
|
Intervention
|
Outcomes in patients with ICH
|
|
INTERACT2
Anderson et al (2013)[35]
|
2,839
|
Blood pressure reduction to goal SBP < 140 mm Hg within 6 h of onset
|
Found to be safe. Did not reduce severe disability or death
|
|
STICH II
Mendelow et al (2013)[36]
|
601
|
Early surgery vs. conservative treatment
|
No clear benefit from early surgery
|
|
MISTIE III
Hanley et al[39]
|
Projected 500
|
Minimally invasive surgery plus rt-PA
|
Currently enrolling
|
|
CLEAR III
Ziai et al (2013)[38]
|
Projected 500
|
rt-PA in patients who require EVD for obstructive hydrocephalus due to 3rd or 4th ventricular blood
|
Currently enrolling
|
|
ATACH2
Qureshi et al (2011)[37]
|
Projected 1280
|
Blood pressure reduction to goal SBP < 140 mm Hg within 3.5 h of onset
|
Currently enrolling
|
Abbreviations: EVD, extraventricular drain; ICH, intracerebral hemorrhage; rt-PA,
recombinant tissue plasminogen activator; SBP = systolic blood pressure.
