Diagnosis and management of spontaneous intracerebral hemorrhage

Recent Findings: Blood pressure reduction likely improves outcomes in patients with intracerebral hemorrhage, although not by the expected mechanism of reducing hematoma growth.. Many ol

Diagnosis and Management of Spontaneous

Intracerebral Hemorrhage

Andrew M Naidech, MD, MSPH, FANA

ABSTRACT

Purpose of Review: This article updates neurologists on recent insights and man-agement strategies of intracerebral hemorrhage (ICH).

Recent Findings: Blood pressure reduction likely improves outcomes in patients with intracerebral hemorrhage, although not by the expected mechanism of reducing hematoma growth One formulation of prothrombin complex concentrate for revers-ing severe bleedrevers-ing associated with warfarin is now approved by the US Food and Drug Administration (FDA), and specific reversal therapies for the novel oral anticoagulants are in development Neurologic monitoring frequently detects ICH worsening that re-quires an intervention Platelet transfusion and pharmacologic platelet activation are promising and often used as part of patient management but have not yet been shown

to improve patient outcomes.

Summary: Measurable progress continues toward establishing effective therapies to improve outcomes in patients with ICH Blood pressure reduction and reversal of med-ications that exacerbate bleeding are likely to improve outcomes Recommendations for neuromonitoring will help clinicians at the bedside attend to the most important ab-normalities and optimize later quality of life This article reviews standards for diagnosis and severity of ICH, monitoring and treatment of complications in the hospital, available interventions, and the measurement of outcomes.

Continuum (Minneap Minn) 2015;21(5):1228–1298.

INTRODUCTION Intracerebral hemorrhage (ICH) is the most deadly form of stroke and leaves many of its survivors with a persistent neurologic deficit Despite the high toll

of the disease, the field continues to improve in diagnosis, targeted neuro-monitoring, and patient management

DIAGNOSIS ICH is less common than acute ische-mic stroke but has a substantially higher acute mortality and a higher rate of early

clinical decompensation1 and is more likely to cause subsequent disability.2 Consequently, misdiagnosis is poten-tially catastrophic The clinical presen-tation is often similar to ischemic stroke

in that patients usually present with a focal neurologic deficit, but are more likely to have very elevated blood pres-sure; altered consciousness; and head-ache, nausea, or vomiting

The etiology of ICH depends on the population ICH in younger popu-lations is more likely due to chronic

Address correspondence to

Dr Andrew M Naidech, 710

N Lake Shore Drive 11th floor,

Chicago, IL 60611,

a-naidech@northwestern.edu.

Relationship Disclosure:

Dr Naidech reports no disclosure.

Unlabeled Use of

Products/Investigational

Use Disclosure:

Dr Naidech discusses the

unlabeled/investigational use

of desmopressin for the

treatment of acute

intracerebral hemorrhage.

* 2015, American Academy

of Neurology.

1288

hypertension, and the hematoma is

more likely to be in the basal ganglia

or brainstem ICH in older populations

is more likely to be lobar (This article

does not consider traumatic ICH.) Many

older patients with lobar hematomas

will meet criteria for probable cerebral

amyloid angiopathy (age at least 55 years,

appropriate clinical history, evidence

of multiple cerebral hemorrhages on

MRI), a condition of amyloid

deposi-tion in cerebral vessels, and these

pa-tients are more likely to be harmed by

anticoagulant medication.3Ataxia may

be the presenting symptom in patients

with cerebellar hematomas, and these

patients should be considered for early

surgical decompression if there is

con-cern for brainstem compression

Imaging

The diagnosis of ICH is established by

an appropriate clinical history with

cor-roborating imaging evidence of

hem-orrhage on CT or MRI scanning MRI

scanning should be performed to help

de-termine the etiology of ICH (Figure 2-1)

Blood vessel imaging with magnetic resonance angiography (MRA), CT angiography (CTA), or conventional angiography should be considered if there is a question of a vascular malfor-mation such as an aneurysm or arterio-venous malformation The yield of angiographic studies in patients with a history of hypertension and a typical appearance of ICH due to hypertension

is very small

Hematomas frequently expand after the diagnostic CT scan, particularly in patients who present soon after symp-tom onset; patients with hemasymp-toma expansion have a substantially worse outcome Thus, minimizing hematoma expansion is a primary goal of acute ICH treatment and the driving force behind aggressively lowering blood pressure and reversing coagulopathy

After the diagnostic CT scan, at least one more brain imaging study should

be performed in symptomatic patients

to determine final hematoma size and assess for hematoma expansion

KEY POINT

desirable to help determine the etiology

of intracerebral hemorrhage and is particularly helpful for cerebral amyloid angiopathy.

FIGURE 2-1 Using MRI to improve diagnosis of intracerebral hemorrhage A, The patient presented with a small lobarintracerebral hemorrhage, seen as hyperdensity on noncontrast CT B, MRI revealed a second hematoma, seen

as dark (hypointense) signal on gradient echo sequence in the left temporal lobe (arrow) Given the patient’s age, these findings made the diagnosis of amyloid angiopathy likely C, Later that month, noncontrast CT performed

when the patient presented with right-sided weakness showed spontaneous hemorrhage in another location with

intraventricular extension.

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SEVERITY OF ILLNESS The Joint Commission has adopted the ICH Score as a standard severity-of-illness scoring system for patients with ICH, and its documentation will

be required at comprehensive stroke centers.4 Scores range from 0 (least severe with low expected mortality)

to 6 (the worse possible score with death likely) Modifications to the ICH score that take into account more clinical or imaging variables may have slightly better predictive value for out-comes (Table 2-1)

Do-not-resuscitate (DNR) status is a known confounder of outcomes in pa-tients with ICH Unsurprisingly, in some (but not all) centers, patients with DNR status receive fewer interventions and have higher mortality rates than patients with a similar severity of injury This is not due to the withholding of any single beneficial intervention for ICH but may

be owing to a pattern of less-aggressive care DNR status should be considered

with the patient and representatives while being mindful of its potential im-pact on subsequent care and outcomes NEUROMONITORING

Many ‘‘neuromonitors’’ exist, ranging from repeated examinations such as level of consciousness2 and delirium screening to invasive monitors.5,6As a general guide, all patients with acute ICH should be admitted to an inten-sive care unit setting to assess for neu-rologic deterioration, although some patients may be triaged to a stroke unit

or step-down intensive care unit based

on clinical severity and resource avail-ability (Figure 2-2)

The field of neuromonitoring has re-cently been exhaustively reviewed by the Neurocritical Care Society.7 Strong rec-ommendations include the following:

& Invasive blood pressure monitoring helps patients who are hemodynamically unstable and helps establish goals that take cerebral perfusion into account

& Oximetry and capnography (measurement of carbon dioxide concentration in the blood) are helpful for mechanically ventilated patients There is enthusiasm, but still only preliminary data, for the use of brain oxygen tension monitors

& Electroencephalography is recommended to detect subclinical seizures in patients with persistently altered consciousness (Case 2-1)

& Blood glucose levels should be routinely measured

& For patients whose body temperature is being actively managed (eg, cooling blankets, intravascular devices), shivering should be regularly monitored with

a standard scale

These recommendations may be re-considered in light of locally available

KEY POINTS

Hemorrhage Score is

required documentation

at comprehensive

stroke centers for

patients with

intracerebral hemorrhage.

encompasses a range of

techniques and data.

Neuromonitoring may

refer to repeated

neurological assessments

(eg, level of alertness,

orientation) over time, to

repeated noninvasive

measures (such as

processed scores from

EEG data), to invasive

monitors that

display brain-specific

measurements.

TABLE 2-1 Intracerebral

Hemorrhage Scorea

Variable

ICH Score Points

Hematoma volume Q30 mL

1

Glasgow Coma Scale 3 or 4

2

Glasgow Coma Scale 5Y12

1

Infratentorial hematoma location

1

Intraventricular hemorrhage

1

ICH = intracerebral hemorrhage.

a Modified with permission from Hemphill JC 3rd, et al, Stroke 4B 2001 American Heart

Association, Inc stroke.ahajournals.org/content/

32/4/891.full.

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resources and may not be possible in

all settings Some monitoring systems

are very resource intensive in terms of

skilled labor and equipment

INTRAVENTRICULAR HEMORRHAGE

Intraventricular hemorrhage (IVH), the

spread of blood into the ventricular

system, is more common with hema-toma locations that are closer to the ventricular system, such as the thalamus and caudate nuclei IVH is a common and serious complication of ICH that may lead to reduced consciousness, hydro-cephalus, fever, and a worse outcome

For patients with small to moderate

FIGURE 2-2 Algorithm of care for intracerebral hemorrhage from presentation throughhospital discharge and follow-up.

CT = computed tomography; EEG = electroencephalogram; ICH = intracerebral hemorrhage; ICU = intensive care unit; MRI = magnetic resonance imaging.

Case 2-1

A 54-year-old woman presented with a new left-sided hemiparesis Her blood

pressure was 140/80 mm Hg, and her history was significant for hypertension.

During the initial examination, the patient required stimulation to attend

to the examiner and to follow voice commands When aroused, she was

oriented to the hospital On physical examination, there was weakness of the

left face, arm, and leg with moderate dysarthria and neglect to sensation.

There was no aphasia or ataxia CT scanning revealed a 15-mL right-sided

lobar hematoma Initial laboratory studies were unremarkable.

Continued on page 1292

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intraparenchymal hematomas and sub-stantial amounts of IVH, intraventricular clot-busting therapy involves removing

a small volume of CSF via the external ventricular drain with a syringe and re-placing it with alteplase and sterile flush solution This is the rationale behind the phase 3 Clot Lysis: Evaluating Accel-erating Resolution of Intraventricular Hemorrhage (CLEAR-IVH) trial, currently

in progress Preliminary results have been promising, although this therapy remains investigational pending the outcome

of this ongoing phase 3 clinical trial.8

MEDICAL MANAGEMENT Table 2-2 summarizes the general medi-cal management of ICH

Anticoagulation-Related Intracerebral Hemorrhage

As subclinical atrial fibrillation is found more often, more patients will be prescribed anticoagulant medica-tion.9 The traditional treatment for atrial fibrillation has been warfarin, and ICH is the most feared compli-cation of anticoagulant treatment

When patients taking warfarin experi-ence severe bleeding, fresh-frozen plasma has been typically prescribed

Recently, prothrombin complex

con-centrates have been evaluated as a potentially more effective alternative, and one proprietary formulation (KCentra) has been recently approved by the US Food and Drug Administration (FDA) specifically for reversing bleeding re-lated to warfarin.10This is a general indi-cation, and few patients with ICH were

in the study leading to this approval Trials of novel oral anticoagulants (NOACs) in otherwise healthy patients with atrial fibrillation showed NOACs

to be equivalent or superior to warfa-rin for stroke prevention and to be associated with lower rates of ICH.11,12 However, NOAC-associated ICH may

be difficult to treat This is likely to be especially problematic for older peo-ple, who are more likely to have atrial fibrillation and more likely to die after ICH How best to reverse NOACs is not known, although a specific antidote for dabigatran is the subject of an ongo-ing clinical study

The optimal timing of restarting anti-coagulant medication after ICH is con-troversial, and few data exist to guide management (Case 2-2) A delay of 1 week

to 3 months is considered reason-able, with early anticoagulation favored for patients with a high risk of throm-boembolism, such as patients with

KEY POINTS

clots with fibrinolytics is

an attractive strategy

for the treatment of

intraventricular

hemorrhage, and a

phase 3 trial is

nearing completion.

be emergently reversed

in patients with

intracerebral

hemorrhage; the

optimal agent is not

clear, but most

physicians prefer

prothrombin complex

concentrates over fresh

frozen plasma at

this time.

The patient’s mental status initially waxed and waned, and the patient

no longer followed commands the next day EEG monitoring was initiated due to encephalopathy, and a lateralized rhythmic pattern was seen on the same side as the hematoma After 6 hours of EEG monitoring, a focal seizure

on EEG without a clinical correlate was seen Levetiracetam 1000 mg IV was administered with resolution of electrographic seizures but intermittent rhythmic activity on EEG was still seen Her mental status improved, and she resumed following commands on bedside examination.

Comment Subclinical seizures are common after intracerebral hemorrhage (ICH) and may be reflected as a depressed mental status or a worsening neurologic examination Guidelines do not support the use of prophylactic antiepileptic drugs (AEDs), particularly phenytoin However, AEDs are indicated for clinical or electroencephalographic seizures Patients with lobar hematomas, as in this patient, are at a particularly high risk for seizures New-onset seizures weeks to months after ICH are also common.

Continued from page 1291

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mechanical heart valves or patients with

evidence of new cerebral ischemia on

MRI, and deferred for patients with

evidence of new hemorrhage on

follow-up MRI scanning In the absence

of clear guidelines and because of

often competing therapeutic concerns

(eg, anticoagulation to prevent

cardio-embolism, deferred anticoagulation to

minimize the risk of recurrent ICH),

this decision is often made after

discus-sion among the consulting physicians

Blood Pressure Reduction

A prevailing theory has been that

he-matoma expansion indicates a physical

tear in an artery or arteriole and that

in-creased blood pressure leads to greater

blood flow out of the tear into brain

pa-renchyma Thus, aggressively reducing

blood pressure might reduce hematoma

expansion and improve functional

out-comes The Intensive Blood Pressure

Reduction in Acute Cerebral Hemor-rhage (INTERACT) trial suggested this hypothesis was valid, with less propor-tional hematoma growth in patients with more aggressive blood pressure reduction (target systolic 140 mm Hg

or less).13 This formed the basis for INTERACT2, which enrolled nearly 2800 patients with acute ICH INTERACT2 did not achieve the primary end point

of improved odds of ‘‘good outcome,’’

which was defined as moderately severe disability or better at 90 days Neither did aggressive blood pressure reduc-tion have an effect on hematoma ex-pansion.14 INTERACT2 did, however, find that aggressive blood pressure re-duction was associated with: (1) im-proved functional outcomes when analyzed as an ordinal shift toward lower levels of disability; and (2) im-proved quality of life This implies that there may be another mechanism

TABLE 2-2 General Management of Intracerebral Hemorrhage

and e220 mm Hg, consider lowering to 140 mm Hg For patients presenting with systolic blood pressure

9220 mm Hg, consider aggressive reduction of blood pressure with a continuous IV infusion

of an antihypertensive and frequent blood

devices for temperature control (preferably avoiding sedation, as appropriate)

320 mOsm/L with weaning over several days

Deep venous thrombosis

prevention

Consider mechanical prophylaxis; consider chemoprophylaxis after hematoma size stable for 2Y3 days

IV = intravenous.

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accounting for a slight benefit from aggressive blood pressure reduction other than reduction in hematoma growth INTERACT2 has been influen-tial, particularly given the lack of other available interventions to improve out-comes after ICH

Patients with ICH and a long history

of hypertension may have an auto-regulatory curve that is shifted to the right (ie, have cerebral vessels that ef-fectively regulate cerebral blood flow

at hypertensive blood pressures but autoregulate less effectively at normal blood pressure) However, blood pres-sure reduction (down to a systolic blood pressure of 140 mm Hg) does not seem

to cause perihematomal ischemia or neurologic decline.14,15 Small areas of ischemia distant from the hematoma have been reported with aggressive blood pressure reduction.16,17

Fever and Temperature Control Temperature should be routinely mea-sured in patients with ICH Where avail-able, a core measure using a bladder catheter is preferred; however, proto-cols to reduce the use of indwelling bladder catheters to minimize infection risk may make this difficult in awake patients Fever (ie, elevated core tem-perature) has been repeatedly linked

to worse outcomes in patients with ICH.18Fever has many deleterious ef-fects, including increased brain and muscle metabolism that may, in turn, have additional adverse consequences Documented associations between fever and worse outcome have led clin-icians to attempt to reduce fever, which has been more difficult and, thus far, less rewarding than initially hoped.19 Antipyretics are routinely given but are typically insufficient to abolish fever A

KEY POINT

outcomes in patients

with intracranial

hemorrhage; whether

aggressive measures to

abolish fever improves

outcomes in these

patients is not clear.

Case 2-2

A 75-year-old man presented with new-onset headache and right hemiparesis with onset 45 minutes prior to presentation to the emergency department His history was significant for hypertension and atrial fibrillation, for which he took warfarin Blood pressure was 185/95 mm Hg, and his temperature was 37.2-C (99.0-F) Physical examination confirmed the right hemiparesis with moderate sensory loss; he followed commands, uttered inappropriate words, and required stimulation to open his eyes (Glasgow Coma Scale score of 11) A CT scan revealed a 34-mL left parietal lobe hematoma with scant intraventricular hemorrhage His Intracerebral Hemorrhage (ICH) Score was recorded as 3 (1 point for a Glasgow Coma Scale

of 11, 1 point for hematoma volume of greater than 30 mL, 1 point for intraventricular hemorrhage [IVH]).

The patient’s blood pressure was reduced to 140 mm Hg systolic Warfarin was reversed with prothrombin complex concentrate Fever developed on day 3 and was treated with acetaminophen Altered mental status prompted EEG monitoring, which was discontinued after 48 hours when no epileptiform abnormalities were seen Repeat CT scanning demonstrated minimal hematoma growth, and an MRI revealed no other foci of intracerebral hemorrhage The patient was discharged to a rehabilitation facility At 1 month, he was awake, alert, and able to ambulate with a device Plans were being made to return home with outpatient physical and occupational therapy Warfarin was restarted Comment When to restart anticoagulation in patients with ICH is not well defined One month is generally considered a reasonable time frame

in patients considered to be a low risk for recurrent ICH.

1294

variety of cooling devices are available,

some external and some intravascular

Cold saline also acutely reduces core

temperature and is a common

inter-vention for temperature reduction after

cardiac arrest.20,21Devices generally are

effective in reducing temperature in

pa-tients with fever that persists despite

antipyretic medication, but shivering

is a common result that may prevent

fever control Shivering can be reliably

assessed at the bedside, and a variety

of off-label medications (eg, buspirone,

fentanyl, meperidine) and interventions

(such as counterwarming with warm air)

have been proposed to minimize

shiv-ering; none are FDA-approved for this

indication.22Y24As of yet, high-quality data

on whether interventions to reduce fever

improve outcomes after ICH are lacking,

although several studies are under way

Cerebral Edema

Cerebral edema is common after ICH

In general, the volume of cerebral

edema is proportional to the volume

of the hematoma, with larger

hema-tomas leading to more edema This is

particularly important in patients with

hematomas large enough to cause

mid-line shift and altered consciousness The

exact cause of cerebral edema is not

clear; ischemia around the hematoma

does not seem to be a proximate cause

Cerebral edema is commonly

visu-alized as hypodensity surrounding the

hematoma on CT or hyperintensity on

T2-weighted MRI, and usually peaks

sev-eral days after ICH onset Treatment

usually consists of hyperosmolar

ther-apy with hypertonic saline, mannitol,

or both Mannitol can be given via

pe-ripheral IV but may lead to volume

de-pletion with repeated dosing because

it is an osmotic diuretic Hypertonic

saline requires a central venous

cathe-ter but can be used indefinitely A target

serum osmolality of approximately

320 mOsm/L (to avoid nephrotoxicity),

or resolution of clinical symptoms, is the usual target of therapy Evidence-based protocols for discontinuation

of hyperosmolar therapy have not been developed; the usual practice is to per-mit serum osmolality to decrease by up

to 10 mEq/L/d as long as there are no symptoms of recurrent cerebral edema

For more information, refer to the article ‘‘Management of Intracranial Pressure’’ by W David Freeman, MD, FSNS, FAAN, in this issue ofContinuum

Antiplatelet Medication and Platelet-Activating Therapy Clinical interventions to improve plate-let activity are analogous to correcting coagulopathy in patients with ICH As anticoagulants lead to reduced blood clotting, aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) lead to platelet inhibition that reduces the for-mation of a platelet plug at the site of bleeding The use of aspirin and NSAIDs can be detected on rapid point-of-care testing in patients with acute ICH.25 When detected, reduced platelet activ-ity is associated with more IVH, more hematoma growth, increased mortality

at 14 days, and worse functional out-comes at 3-month follow-up.26,27 Interventional trials to improve plate-let activity are under way Plateplate-let trans-fusion was a logical step to improve platelet activity and improves point-of-care assay results A prospective, ran-domized controlled trial of platelet transfusion (PATCH) is under way in Europe.28 Pending these data, platelet transfusion for ICH has become com-monplace in some centers.29However, platelet transfusion has potential ad-verse events, such as infection, volume overload, and limited supply Des-mopressin has been prescribed for more than 2 decades to improve plate-let activity in patients known to take aspirin In a recent phase 2a trial, it im-proved platelet activity in patients with acute ICH.30,31

KEY POINT

common after intracerebral hemorrhage and generally reflects the volume of the underlying hematoma.

1295

Statins

("-Hydroxy-"-Methylglutaryl-CoA Reductase Inhibitors) Controversy has surrounded the use

of statin drugs in patients at high risk for ICH, particularly lobar ICH.32 This was buttressed by data showing an as-sociation between aggressively lower-ing cholesterol and a higher risk of ICH.33More recent data suggest statins may be associated with no harm and perhaps better outcomes after ICH.34,35 Withholding or reducing the dose in patients with ICH and very low density lipoprotein cholesterol seems prudent

Otherwise, discontinuation of statins does not appear to be necessary in most ICH patients

SURGICAL MANAGEMENT

A working relationship with neurosur-gical colleagues is crucial to maximizing outcomes for patients with ICH Partic-ular consideration should be given to the following:

& Patients with cerebellar hematomas since these patients are at a high risk for brainstem compression

& Large lobar hematomas since these are most accessible

& Ventricular drainage for patients with hydrocephalus or IVH

& Patients with midline shift, as this may be surgically correctable

& A decrease in consciousness on serial neuromonitoring, as this may indicate an expanding intracranial hematoma Other than patients who are highly likely to clinically benefit from surgical decompression (eg, large cerebellar hematomas, hemispheric hematomas causing tissue shift, and neurologic de-cline in patients with good rehabilitation potential), the best way to select patients for surgical decompression is less clear

In patients without a clear need for emergent surgical decompression, two

clinical trials of early surgery (via crani-otomy) versus expectant management found no difference in outcomes.36 He-matoma evacuation by means of stereo-taxis is currently being investigated in the Minimally Invasive Surgery Plus rt-PA for Intracerebral Hemorrhage Evacuation (MISTIE) trial.37

ANALYSIS OF OUTCOMES DATA The most common outcome metric for ICH is the modified Rankin Scale (mRS),

a global functional scale from 0 (no symp-toms) to 6 (dead) The mRS has a high inter-rater reliability when validated ques-tionnaires are used for its assessment, so different raters will generally record the same result.38

A variety of scores for health-related quality of life are also available and are generally correlated with the mRS The National Institutes of Health (NIH) has recently released novel outcome measures: Neuro-QOL is a series of questionnaires specifically developed and validated in patients with neuro-logic diseases.39The Patient-Reported Outcomes Measurement Information System has more general instruments, many of which ‘‘cross-walk’’ to Neuro-QOL measures The NIH Toolbox is a set of performance measures in mo-tor, cognitive, sensory, and self-reported emotional health.40 These low-cost, web-based tools make it possible for more centers to comprehensively obtain state-of-the-art outcomes and examine how their processes might maximize health-related quality of life (www.assessmentcenter.net)

CONCLUSION Care of patients with acute ICH has been improved by better description of severity and complications, evolutions

in monitoring and control of vital signs, and measurable improvements in out-comes with specific interventions The

KEY POINTS

consultation is

particularly indicated for

cerebellar hemorrhage,

large lobar hemorrhage,

hydrocephalus, midline

shift, and a decrease in

consciousness on

serial neuromonitoring.

Patient-Reported

Outcomes Measurement

Information System,

and National Institutes

of Health Toolbox are

web-based outcome

measures developed by

the National Institutes

of Health.

1296

next several years are likely to see

fur-ther advancements that improve

func-tional outcomes and quality of life for

survivors of ICH

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