Intracranial Hemorrhage

a b,c,
J. Alfredo Caceres, MD , Joshua N. Goldstein, MD, PhD *

KEYWORDS
 Intracranial hemorrhage  Acute stroke  Intracerebral hemorrhage
 Subarachnoid hemorrhage

KEY POINTS
 Intracerebral hemorrhage is the most devastating form of stroke, with high mortality and
severe disability among survivors.
 While no single therapy has been demonstrated to improve outcome, there is evidence
that high quality supportive care can provide substantial benefit.
 National evidence-based guidelines are available to guide management for both intrace-
rebral hemorrhage and subarachnoid hemorrhage.
 Ruptured aneurysms are best managed by teams with experience in both surgical and en-
dovascular techniques.

INTRODUCTION

Intracranial hemorrhage refers to any bleeding within the intracranial vault, including
the brain parenchyma and surrounding meningeal spaces. This article focuses on
the acute diagnosis and management of primary nontraumatic intracerebral hemor-
rhage (ICH) and subarachnoid hemorrhage (SAH) in emergency departments (EDs).

INTRACEREBRAL HEMORRHAGE

ICH is a devastating disease. The overall incidence of spontaneous ICH worldwide is

24.6 per 100,000 person-years with approximately 40,000 to 67,000 cases per year in
the United States.1–3 The 30-day mortality rate ranges from 35% to 52% with only
20% of survivors expected to have full functional recovery at 6 months.3 Approxi-
mately half of this mortality occurs within the first 24 hours,4 highlighting the critical
importance of early and effective treatment in EDs.

Risk Factors
A recent population-based meta-analysis showed that risk factors for ICH include male
gender, older age, and Asian ethnicity.1,5 ICH is twice as frequent in low-income to

a
Department of Neurology, Massachusetts General Hospital, Suite 3B, Zero Emerson Place,
Boston, MA 01940, USA; b Harvard Medical School, 25 Shattuck Street, Boston, MA 02115,
USA; c Department of Emergency Medicine, Massachusetts General Hospital, Suite 3B, Zero
Emersion place, Boston, MA 01940, USA
* Corresponding author.
E-mail address: [email protected]

Emerg Med Clin N Am 30 (2012) 771–794

http://dx.doi.org/10.1016/j.emc.2012.06.003 emed.theclinics.com
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772 Caceres & Goldstein

middle-income countries compared with high-income countries.5 In the United States,

several studies have shown that the incidence of ICH is greater in African Americans
and Hispanics than in whites.6–8
The most important risk factors for ICH include hypertension (HTN) and cerebral
amyloid angiopathy (CAA). HTN-related ICH is more likely to occur in deep structures,9
and the risk of ICH increases with increasing blood pressure (BP) values.10 CAA tends
to occur in association with advanced age, and CAA-related ICH tends to occur in
lobar regions.11
Other risk factors for ICH include

1. Alcohol intake: this risk seems dose-dependent, with a higher risk of ICH among
those with a higher daily alcohol intake.10 Acute changes in BP during ingestion
and withdrawal, effects on platelet function and coagulation, and dysfunction of
the vascular endothelium may account for this risk.12
2. Cholesterol: low levels of total serum cholesterol are risk factors for ICH (in contrast
to ischemic stroke, for which high cholesterol levels are a risk).13
3. Genetics: the gene most strongly associated with ICH is the apolipoprotein E gene
and its ε2 and ε4 alleles.14 The presence of the ε2 allele was recently also linked to
hematoma expansion.15
4. Anticoagulation: oral anticoagulants are widely used as prophylaxis in patients with
atrial fibrillation and other cardiovascular and prothrombotic states. The annual risk
of ICH in patients taking warfarin ranges from 0.3% to 1.0% per patient-year, with
a significantly increased risk when the international normalized ratio (INR) is greater
than 3.5.16
5. Drug abuse: sympathomimetic drugs, such as cocaine, are risk factors for ICH, and
patients actively using cocaine at the time of their ICH have significantly more
severe presentations and worse outcomes.17

Pathophysiology
Primary ICH is typically a manifestation of underlying small vessel disease. First, long-
standing HTN leads to hypertensive vasculopathy, causing microscopic degenerative
changes in the walls of small-to-medium penetrating vessels, which is known as lip-
ohyalinosis.18 Second, CAA is characterized by the deposition of amyloid-b peptide
in the walls of small leptomeningeal and cortical vessels.19 Although the underlying
mechanism leading to the accumulation of amyloid is still unknown, the final conse-
quences are degenerative changes in the vessel wall characterized by the loss of
smooth muscle cells, wall thickening, luminal narrowing, microaneurysm formation,
and microhemorrhages.20
After initial vessel rupture, the hematoma causes direct mechanical injury to the brain
parenchyma. Perihematomal edema develops within the first 3 hours from symptom
onset and peaks between 10 and 20 days.21 Next, blood and plasma products mediate
secondary injury processes, including an inflammatory response, activation of the
coagulation cascade, and iron deposition from hemoglobin degradation.21 Finally, the
hematoma can continue to expand in up to 38% of patients during the first 24 hours.22

Clinical Presentation and Diagnosis

The acute presentation of ICH can be difficult to distinguish from ischemic stroke.
Symptoms may include headache, nausea, seizures, and focal or generalized neuro-
logic symptoms. Findings, such as coma, headache, vomiting, seizures, neck stiff-
ness, and raised diastolic BP, increase the likelihood of ICH compared with
ischemic stroke, but only neuroimaging can provide a definitive diagnosis.23
 Intracranial Hemorrhage 773

Neuroimaging
Noncontrast CT
Noncontrast CT is the most rapid and readily available tool for the diagnosis of ICH24
and remains the most commonly used technique in the ED. Besides providing the
definitive diagnosis, CT may also show basic characteristics of the hematoma, such
as hematoma location, extension to the ventricular system, presence of surrounding
edema, development of mass effect, and midline shift.
A quick estimation of the hematoma volume can be rapidly performed in an ED with
the validated ABC/2 technique (Fig. 1).25 The steps to follow using this technique are
 The CT slice with the largest area of hemorrhage is selected.
 A is the largest hemorrhage diameter on the selected slice (in centimeters [cm]).
 B is the largest diameter perpendicular to A on the same slice.
 C is the approximate number of slices in which the hemorrhage is seen multiplied
by the slice thickness (often 0.5-cm slices).
 A, B, and C are multiplied and the product divided by 2.

CT angiography
CT angiography (CTA) is gaining increasing acceptance as a diagnostic tool in the
acute setting.26 It is the most widely available, noninvasive technique for ruling out
vascular abnormalities as secondary causes of ICH. The risk of acute nephropathy,
if any, is likely low.27 Up to 15% of patients with ICH show an underlying vascular
etiology on CTA, potentially changing acute management.28 Finally, contrast extrava-
sation seen on CTA images, also known as a spot sign (Fig. 2), is thought to represent
ongoing bleeding and seems to mark those patients at highest risk of hematoma
expansion and with poor outcome and mortality.29–32

MRI
MRI is equivalent to CT for the detection of acute ICH.33 The imaging characteristics of
ICH vary with time as the hemoglobin passes through different stages during the

Fig. 1. ABC/2 technique. (From Li N, Wang Y, Wang W, et al. Contrast extravasation on

computed tomography angiography predicts clinical outcome in primary intracerebral
hemorrhage. Stroke 2011;42:3441–6; with permission.)
774 Caceres & Goldstein

Fig. 2. CT and CTA of acute ICH. (A) Noncontrast CT shows a right thalamic ICH (24 mL) with
associated IVH (6 mL). (B) CTA demonstrates 3 foci of contrast (spot signs) within the ICH (arrow-
heads) (C). Delayed CTA shows increased volume and changed morphology of the spot signs
(arrowheads). (D) Noncontrast CT after 8 hours demonstrates expansion of the ICH (94 mL)
and IVH (82 mL). (From Kidwell CS, Chalela JA, Saver JL, et al. Comparison of MRI and CT for
detection of acute intracerebral hemorrhage. JAMA 2004;292[15]:1823–30; with permission.)

pathologic process. In the acute phase, gradient-recalled-echo imaging techniques

with T2* weighting are the best option to detect the presence of ICH.34 MRI can
also detect underlying secondary causes of ICH, such as tumor and hemorrhagic
transformation of ischemic stroke. Finally, for patients with poor kidney function or
contrast allergies, the cerebral vasculature can be analyzed without contrast using
time-of-flight magnetic resonance angiography.35

Acute Management
Airway
Patients with ICH are often unable to protect the airway. Endotracheal intubation may
be necessary but this decision should be balanced against the risk of losing the
 Intracranial Hemorrhage 775

neurologic examination. Rapid sequence intubation is typically the preferred approach

in the acute setting. Pretreatment with lidocaine may be considered because it may
blunt a rise in intracranial pressure (ICP) associated with intubation. Paralytic agents
include succinylcholine, rocuronium, and vecuronium, and, for postintubation seda-
tion, propofol is a reasonable choice, given its short half-life.36,37

Blood pressure management

Elevated BP is common in the acute setting after an ICH, and higher BP levels are
associated with hematoma expansion and poor prognosis. It is not clear, however,
that reducing BP improves outcomes.38 Although lowering BP may reduce the risk
of expansion, it may theoretically also reduce cerebral perfusion. One randomized
clinical trial found that lowering systolic BP (SBP) to 140 mm Hg compared with 180
mm Hg reduced the risk of hematoma expansion but had no effect on outcomes.39
A second trial found that rapid BP lowering using intravenous nicardipine seems
safe but again showed no difference in outcomes.40 Several clinical trials are currently
ongoing to address this issue.41–43
Until these trials clarify the role of BP management on hematoma expansion,
expert guidelines from the American Heart Association/American Stroke Association
(AHA/ASA) recommend BP treatment (Box 1).38 The European Stroke Initiative
(EUSI) guidelines are similar (Table 1).44
In choosing medications to manage HTN, intravenous antihypertensives with short
half-lives should be considered as first-line therapy. The AHA recommends consid-
ering IV labetalol, nicardipine, esmolol, enalapril, hydralazine, sodium nitroprusside,
or nitroglycerin.38 The EUSI recommends IV labetalol, urapidil, sodium nitroprusside,
nitroglycerin, or captopril.44

Hemostatic therapy
It is tempting to consider that in a patient with ICH, acute hemostatic therapy will
provide benefit. One phase III randomized trial in patients with no underlying coagul-
opathy found no clinical benefit from this approach.45 As a result, current approaches
to hemostasis are focused on correcting any underlying coagulopathies.

Oral anticoagulation The most common class of agent used for oral anticoagulation is
warfarin. Many investigators believe that early action to rapidly correct the coagulop-
athy may prevent continued bleeding.46 Several therapeutic options are available for
warfarin reversal.

Box 1
Recommended guidelines from the AHA/ASA for treating elevated BP in spontaneous ICH

1. If SBP is >200 mm Hg or mean arterial pressure (MAP) is >150 mm Hg, then consider
aggressive reduction of BP with continuous intravenous infusion, with frequent BP
monitoring every 5 minutes.
2. If SBP is >180 mm Hg or MAP is >130 mm Hg and there is the possibility of elevated ICP, then
consider monitoring ICP and reducing BP using intermittent or continuous intravenous
medications while maintaining a cerebral perfusion pressure (CPP) 60 mm Hg.
3. If SBP is >180 mm Hg or MAP is >130 mm Hg and there is no evidence of elevated ICP, then
consider a modest reduction of BP (eg, MAP of 110 mm Hg or target BP of 160/90 mm Hg)
using intermittent or continuous intravenous medications to control BP and clinically re-
examine the patient every 15 minutes.

Adapted from Morgenstern LB, Hemphill JC III, Anderson C, et al. Guidelines for the manage-
ment of spontaneous intracerebral hemorrhage. Stroke 2010;41(9):2108–29; with permission.
776 Caceres & Goldstein

Table 1
Recommendations from EUSI for BP management in ICH

Previous history of HTN Gradually reduce MAP to <120 but >84 mm Hg; avoid
a reduction of >20%.
BP limit is <180/105 mm Hg; target should
be <170/100 mm Hg. Avoid a reduction of >20%.
No history of HTN Reduce MAP to 110 mm Hg.
BP limit is <160/95 mm Hg; target should be
<150/90 mm Hg. Avoid a reduction of >20%.
When increased ICP is present Adapt MAP and BP limits to target a CPP of 60–70 mm Hg.

Data from Steiner T, Kaste M, Forsting M, et al. Recommendations for the management of intracra-
nial haemorrhage—part I: spontaneous intracerebral haemorrhage. The European Stroke Initiative
Writing Committee and the Writing Committee for the EUSI Executive Committee. Cerebrovasc Dis
2006;22(4):294–316.

Because warfarin inhibits the vitamin K–dependent carboxylation of factors II, VII,
IX, and X, vitamin K is a first-line agent to restore these factors. Vitamin K given intra-
venously lowers the INR as early as 4 hours but requires more than 24 hours for full
effect when used as monotherapy.47 Vitamin K infusion at a dose of 5 mg to 10 mg
should be started promptly and given slowly over 30 minutes.48,49
While awaiting the effect of intravenous vitamin K, coagulation factors should be
infused emergently. Fresh frozen plasma (FFP) contains all coagulation factors and is
the most widely available and commonly used agent in the United States.50 Limitations
include adverse events, such as allergic reactions, potential transmission of infectious
agents, and transfusion-related acute lung injury.51 There is also significant time
needed for its administration in actual practice, including time spent ordering, match-
ing, thawing, and delivering to an ED.50 The dose of FFP ranges from 10 mL/kg to 20
mL/kg of body weight. On average, the volume needed to correct the INR varies from
800 mL to 3500 mL, which may impose a significant volume load.52 Early administration
of coagulation factors maximizes the opportunity for early INR correction.53
Prothrombin complex concentrates (PCCs) provide an alternate source of coagula-
tion factors. PCCs contain coagulation factors prepared from pooled plasma. All avail-
able PCCs contain factors II, IX, and X, and some contain relevant amounts of factor
VII and proteins C and S. In the United States there are currently 2 commercially avail-
able PCCs, Bebulin VH Factor IX Complex (Baxter, Westlake, California) and Profilnine
SD (Grifols Biologicals, Los Angeles, California).54 Many other products are available
in other countries, including Octaplex (Octapharma) and Beriplex (CSL Behring, King
of Prussia, PA, USA), which include clinically relevant amounts of all 4 vitamin K–
dependent factors, sometimes termed, 4-factor PCCs, to differentiate them from
the other 3-factor PCCs.55 PCC offers several advantages over FFP, including smaller
infusion volume, faster time to INR correction, and lack of need for blood type match-
ing.54 Thromboembolic events are potential complications of the use of PCC, although
it is not clear that this risk (approximately 1.9%) is any different with FFP.56,57

Heparinoids Heparin-related ICH is rare and data are sparse regarding appropriate
treatment. One reasonable approach would be to reverse heparin with IV protamine
sulfate at a dose of 1 mg to 1.5 mg per 100 units of heparin with a maximum dose
of 50 mg.58

Platelet function The 2 major causes of platelet dysfunction are antiplatelet therapy
and thrombocytopenia.
 Intracranial Hemorrhage 777

Antiplatelet agents use before an ICH is associated with a small increase in mortality,
suggesting an opportunity for intervention.59 The utility and safety of platelet transfusion
in such patients is unknown, although some laboratory data suggest that such transfu-
sions may improve platelet activity.60 Platelet transfusion is, therefore, considered
investigational by the AHA and is not recommended by the EUSI. The ongoing PATCH
clinical trial will investigate whether platelet transfusions can improve outcome.61
Additionally, it is not clear whether low platelets contribute to ongoing bleeding or
worse outcome. Pending further data, current AHA recommendations are that patients
with severe thrombocytopenia should receive platelet transfusion.38 A specific cutoff
is not clarified; different groups use thresholds between 10,000 and 50,000 per mL.
Novel antithrombotics Recently, several new agents, such as factor Xa inhibitors,
apixaban and rivaroxaban, and the direct thrombin inhibitor, dabigatran, have become
available for stroke prevention.62–64 There is no currently known antidote for reversal of
these agents. Specific hemostatic agents, such as recombinant activated factor VII
and PCCs, may be considered, although there are limited data on their use.65,66 For
those cases related to dabigatran use, a recently published expert recommendation
states that the drug should be stopped immediately, supportive and symptomatic
treatment should be initiated, and, due to its renal excretion, aggressive diuresis
and potential dialysis could be considered.67

Intracranial pressure management

An increase in the ICP may arise from the presence of intraventricular hemorrhage
(IVH) and subsequent hydrocephalus or from mass effect from a large hematoma or
perihematomal edema. Currently, there are limited data regarding indications for
ICP monitoring. Current guidelines from the AHA/ASA suggest that patients with
a Glasgow Coma Scale (GCS) score of less than or equal to 8, those with clinical
evidence of transtentorial herniation, and those with significant IVH or hydrocephalus
should be considered for ICP monitoring and treatment.38 CPP can then be monitored,
and recommendations are to maintain CPP between 50 mm Hg to 70 mm Hg.28
The initial management of elevated ICP should comprise simple measures, such as
elevation of the head of the bed, analgesia, and sedation. Medical options for ICP
treatment include mannitol, hypertonic saline (ranging from 3% to 23.4%), and neuro-
muscular paralysis.3,68,69 Barbiturates can be considered in refractory intracranial
HTN.36 Although hyperventilation can produce a rapid decrease in the ICP, its effects
are temporary, and its use should be reserved for impending herniation while awaiting
surgical decompression.

Hyperglycemia management
Hyperglycemia measured at arrival in the ED is associated with worse outcome in both
nondiabetic and diabetic patients.70,71 Declining glucose values after ICH are associ-
ated with a decreased risk of hematoma expansion and poor outcome, suggesting
that early glucose control may improve outcomes.46 Early evidence for this interven-
tion comes from the Quality in Acute Stroke Care (QASC) trial, in which patients with
ICH and ischemic stroke were randomized to receive standard care, or a set of inter-
ventions aimed at treating fever, hyperglycemia, and performing swallow screens.72
The intervention (including glucose management) lowered mortality, and improved
outcome, highlighting the need for careful glycemic control in the early phase.38

Temperature
The presence of fever is a common finding in patients with ICH, especially in those with
IVH. Again, data from the QASC trial suggest lower mortality and improved outcome in
778 Caceres & Goldstein

those patients receiving fever control as part of a multidisciplinary approach.72 Those

with fever should undergo a thorough investigation to find a fever source if possible.38

Anemia
The presence of anemia is common in patients with ICH. It is present in up to 25% of
cases at admission and is associated with larger hematoma volumes.73 It also
frequently develops during hospital stay.74 Although current guidelines do not address
this issue, a recent study found that packed red blood cell transfusion in these patients
was associated with improved survival at 30 days.74 Therefore, transfusion can be
considered in such patients, although the ideal target hemoglobin level has not
been determined.

Antiepileptics
Patients with ICH are at an increased risk of developing seizures; however, most of
these events are subclinical electroencephalographic findings. Seizures are more
common in lobar ICH and during the first 72 hours after admission.75–77 The majority
of patients develop a single episode of seizure during hospitalization, suggesting that
those episodes are related to the pathophysiologic processes that occur early after an
ICH.77 The use of prophylactic antiepileptic drugs (AEDs) in patients with ICH is
a common practice, although it is not clear that the presence of seizures and/or the
use of prophylactic AEDs affects short-term or long-term outcome.78,79 Some studies
have reported an association between AEDs and worse outcome, although these
patients were disproportionately exposed to phenytoin as the AED of choice.80,81
Currently, the AHA/ASA recommends that AEDs should not be used routinely in
patients with ICH. The only clear indications are the presence of clinical seizures or
electrographic seizures in patients with a change in mental status. They also suggest
that the use of continuous electroencephalography monitoring should be considered
in those patients with depressed mental status out of proportion to the degree of brain
injury.38

Surgical Interventions
External ventricular drain placement
As described previously, some patients may benefit from ICP monitoring. External
ventricular drain placement not only provides the ability to monitor ICP but also has
the advantage of allowing therapeutic drainage of the cerebrospinal fluid (CSF), which
is valuable in patients with hydrocephalus.82 The AHA recommends that ICP moni-
toring and treatment be considered in patients with a GCS score less than or equal
to 8, those with clinical evidence of transtentorial herniation, or those with significant
IVH or hydrocephalus.38 The EUSI recommends considering continuous ICP moni-
toring in patients who need mechanical ventilation and recommends medical treat-
ment of elevated ICP if clinical deterioration is related to increasing edema.44

Intraventricular thrombolysis
IVH occurs when ICH extends into the ventricles. It occurs in approximately 45% of
ICH, more frequently in large and deeply located (caudate nucleus and thalamus)
hemorrhages.83 The presence and the volume of IVH are correlated with poor prog-
nosis in patients with ICH.84 Although evacuation of an intraventricular clot is currently
not routinely recommended, a recent study comparing the use of intraventricular
recombinant tissue plasminogen activator (rtPA) to placebo not only showed that
the use of rtPA was feasible and safe but also showed a significantly greater rate of
blood clot resolution.85 In addition, a recent meta-analysis found that adding intraven-
tricular fibrinolysis to external ventricular drain placement is associated with better
 Intracranial Hemorrhage 779

functional outcome,86 although no prospective randomized trial has evaluated this.

The Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage
(CLEAR III) study, an ongoing phase III randomized clinical trial, was designed to
compare the effect on clinical outcome of the intraventricular use of rtPA compared
with placebo (ClinicalTrials.gov [NCT00784134]).
Hematoma evacuation
The role of surgical evacuation is to decrease mass effect related to the presence of
blood as well as to minimize secondary injury. The only clear recommendation for
immediate surgical intervention is in patients with cerebellar hemorrhages with neuro-
logic deterioration, brainstem compression, and/or hydrocephalus from ventricular
obstruction.38 For these patients, emergency neurosurgical consultation should be
obtained. It is less clear, however, whether patients with supratentorial ICH will
benefit. One large phase III clinical trial, Surgical Treatment for Intracerebral Hemor-
rhage (STICH), compared early hematoma evacuation with initial conservative treat-
ment of patients with spontaneous supratentorial ICH.87 This study showed no
difference in outcome, suggesting that surgical evacuation provided no benefit. A
subsequent subgroup analysis, however, raised the possibility that those with hema-
tomas less than or equal to 1 cm from the cortical surface (which are more easily
accessible) might receive benefit.87 This possibility is being evaluated in the ongoing
STICH II trial.88 The theoretic idea that hyperacute evacuation of the hematoma would
be beneficial was not borne out when a study evaluating the effect of surgery within 4
hours was stopped due to a high rate of rebleeding.89
Minimally invasive surgery
The development of less-invasive surgical techniques may decrease the risk of
surgical complications. These techniques are showing promising results, particularly
in deep hemorrhages where conventional surgery showed no benefit in the past.90
Minimally invasive stereotactic puncture is reported safe and feasible and may lead
to better long-term outcome and fewer complications when compared with conven-
tional craniotomy91 and conventional medical treatment.92,93

Prognosis
Multiple grading scores exist that allow for evidence-based risk stratification in the acute
phase. First, the ICH score predicts 30-day mortality using features, such as age, ICH
volume, and the presence of IVH, with higher score associated with worse outcome
(Table 2).94 Second, the FUNC (functional outcome risk stratification) score predicts
functional independence rather than mortality at 90 days (Table 3).95 The higher the
FUNC score, the greater the chance of the patient recovering functional independence.
There are some data that poor prognosis can lead to self-fulfilling prophecies of
early death. Limiting care via early do-not-resuscitate (DNR) orders, withdrawal of
care, or deferral of other life-sustaining interventions is independently associated
with both short-term and long-term mortality after ICH, after controlling for clinical
markers of disease severity, even in patients who do not specifically require defibrilla-
tion.96 As such, new DNR orders or withdrawal of care is generally not recommended
in the ED. The AHA recommends aggressive full care early after ICH onset with post-
ponement of new DNR orders until at least the second full day of hospitalization.38

SUBARACHNOID HEMORRHAGE

SAH is defined by the extravasation of blood into the subarachnoid space. The most
common cause of SAH is trauma; among nontraumatic cases, rupture of an
780 Caceres & Goldstein

Table 2
The ICH Score

Component ICH Score Points

GCS score
3–4 2
5–12 1
13–15 0
ICH volume (cm3)
30 1
<30 0
IVH
Yes 1
No 0
Infratentorial origin of ICH
Yes 1
No 0
Age (y)
80 1
<80 0

Data from Hemphill JC III, Bonovich DC, Besmertis L, et al. The ICH score: a simple, reliable grading
scale for intracerebral hemorrhage. Stroke 2001;32(4):891–7.

Table 3
The FUNC Score

Component FUNC Score Points

ICH volume (cm3)
<30 4
30–60 2
>60 0
Age (y)
<70 2
70–79 1
80 0
ICH location
Lobar 2
Deep 1
Infratentorial 0
GCS score
9 2
8 0
Pre-ICH cognitive impairment
No 1
Yes 0
Total FUNC score 0–11

Data from Rost NS, Smith EE, Chang Y, et al. Prediction of functional outcome in patients with
primary intracerebral hemorrhage: the FUNC score. Stroke 2008;39(8):2304–9.
 Intracranial Hemorrhage 781

intracranial aneurysm is the leading cause, representing up to 85% of cases. This

review focuses on aneurysmal SAH.
Epidemiology
The overall incidence of SAH is between 9 and 20 per 100,000 person-years. SAH is
more frequent in women, and the mean age of presentation is 55 years.97,98 In the
United States, the number of cases of SAH is 30,000 per year.99
Risk Factors and Prognosis
Major risk factors associated with SAH are current and former history of smoking,
HTN, and excessive alcohol intake.100 Although one-third of cases can be attributed
to a current smoking status, this risk seems to rapidly disappear after a few years of
smoking cessation.101 Cocaine use is also associated with SAH, and patients taking
cocaine tend to be younger and have a worse outcome.102,103 First-degree family
history as well as some genetic conditions, including autosomal dominant polycystic
kidney disease, Marfan syndrome, and Ehlers-Danlos syndrome, are also associated
with an increased risk of SAH.104
A recent meta-analysis reported that in a population without comorbidities, the
prevalence of unruptured intracranial aneurysms is 3.2%.105 Only a small percentage
of these unruptured intracranial aneurysms rupture and cause an SAH. The risk of
rupture is increased in cases of previous history of SAH, age older than 60, female
gender, and Japanese or Finnish descent. In addition, the risk is greater for aneurysms
greater than 10 mm and those located in the posterior circulation.106–108
The introduction of surgical treatment options improved the prognosis of patients
with SAH.109 In a retrospective analysis before the introduction of endovascular treat-
ment of SAH, the most important factors predicting poor outcome at 3 months were
increasing age, worse admission grade on the World Federation of Neurological
Surgeons (WFNS) grading scale (Table 4), the development of cerebral infarction,
and symptomatic vasospasm. Other factors included greater clot thickness on admis-
sion CT scan, aneurysm rupture within the posterior circulation, intraventricular and
intracerebral extension of the hematoma, and higher SBP on admission.110 Analysis
from the large International Subarachnoid Aneurysm Trial (ISAT) comparing neurosur-
gical clipping with endovascular coiling showed similar results.111
Pathophysiology
Aneurysms are more common at the bifurcation of the arteries located on the base of
the brain, especially the large arteries that form the circle of Willis.112 Hemodynamic
factors that contribute to the formation and growth of aneurysms are wall shear stress

Table 4
World Federation of Neurological Surgeons grading scale

WFNS Grade GCS Motor Deficit

1 15 Absent
2 13 to 14 Absent
3 13 to 14 Present
4 7 to 12 Present or absent
5 3 to 6 Present or absent

Data from Report of World Federation of Neurological Surgeons committee on a universal

subarachnoid hemorrhage grading scale. J Neurosurg 1988;68(6):985–6.
782 Caceres & Goldstein

and hydrostatic and transmural pressures. High wall shear stress is encountered at the
branch points of cerebral arteries, and long-term exposure to this could trigger vessel
wall remodeling through interaction with the endothelium and the secretion of factors,
such as nitric oxide and endothelial growth factors. Hydrostatic and transmural pres-
sures produce a mechanical stretch of the wall that induces upregulation of certain
molecules, such as endothelin-1B receptors, that further affect vascular smooth
muscle cells by promoting apoptosis.113 Although the mechanism of formation and
growth of aneurysms is partially understood, it is still unclear what leads to aneurysmal
rupture.

Clinical Presentation
The characteristic complaint of patients with SAH is a severe headache of acute onset.
This headache is commonly described as “the worst headache of my life,” with the
highest intensity at onset. Although it is frequently accompanied by other symptoms,
headache may be the only complaint in up to 40% of patients.114 Recently, a prospec-
tive study found that the following clinical characteristics represent the highest risk of
belonging to a case of SAH: age greater than 40 years, associated neck pain or stiff-
ness, witnessed loss of consciousness, onset with exertion, vomiting, arrival by ambu-
lance, and BP above 160/100.115
A subgroup of patients develops warning signs before the index SAH. The most
common warning sign is again headache, which is of moderate intensity and less
severe than that described in SAH. This is commonly referred to as sentinel headache
or warning leak and may be associated with a small leakage of blood into the
subarachnoid space or a small bleed into the aneurysmal wall. A thorough evaluation
is warranted in these cases, because SAH can develop up to 110 days later.116,117
Physical examination may demonstrate neck stiffness and meningismus.118
Although not specific, funduscopic evaluation may reveal subhyaloid, vitreous, or
intraretinal hemorrhage (known as Terson syndrome), which is associated with higher
mortality.119 These eye findings may be found with any intracranial bleeding and are
believed associated with sudden increase in ICP. Focal neurologic deficits may also
be found and can be related to nerve compression by the aneurysm, intraparenchymal
extension of the bleeding, or vasospasm (which typically occurs later in the course).

Diagnosis
Up to 1 in 20 SAH patients are missed during initial evaluation.120 A high index of
suspicion and a low threshold for performing diagnostic studies are key factors in
making the diagnosis of SAH.
The gold standard diagnostic approach has been to initially perform a noncontrast
CT scan of the brain followed by a lumbar puncture (LP) and analysis of the CSF when
the CT is negative. Recently, however, some groups have suggested that current-
generation multislice CT scanners as well as the availability of CTA in the acute setting
may offer opportunities to selectively defer LP.121,122

CT
When there is clinical suspicion of SAH, the initial test of choice is a noncontrast CT
scan. The sensitivity of the CT scan to detect SAH is maximal within the first 24 hours
after the bleed and then decreases with time. The volume of blood in the
subarachnoid space and the resolution of the scanner also influence the CT detection
rate.123 A recent multicenter prospective study of 3132 patients found that of those
undergoing current-generation CT within 6 hours of symptom onset, the sensitivity
was 100% (95% CI, 97%–100%) with a negative predictive value of 100% (95% CI,
 Intracranial Hemorrhage 783

99.5%–100%).122 Noncontrast CT also provides information regarding the volume of

blood, extension to the cerebral parenchyma, the presence of hydrocephalus, and the
potential location of the aneurysm. Blood located in the interhemispheric fissure and
the surrounding sulci has a high probability of coming from an anterior cerebral or
anterior communicating artery aneurysm, whereas blood in the posterior aspect of
the sylvian fissure is probably related to a middle cerebral artery aneurysm
(Fig. 3).123–125

CT angiography
CTA is a fast, noninvasive, and readily available method to screen for the presence of
aneurysm.126 A recent meta-analysis showed that CTA has a pooled sensitivity of
approximately 98% to detect aneurysm, with sensitivities ranging from 86% to
100%.127 Aneurysm detection rates are related to the experience of the reviewer
and aneurysmal size. Pooled specificity of CTA in this analysis reached 100% with
a range of 50% to 100%.127 Also, 3-D CTA may be as sensitive and specific as digital
subtraction angiography for the detection of aneurysms (Fig. 4).128 As a result,
patients with negative CT/CTA have a less than 1% likelihood of aneurysmal
SAH.121 The Neurocritical Care Society recommends preferential use of CTA as an
exploratory approach when it is readily available and of high technical quality over
digital subtraction angiography if an immediate intervention is not planned.129

Lumbar puncture
LP is considered effectively 100% sensitive for detection of blood in the subarachnoid
space, and it is recommended in all patients undergoing a workup for SAH with a nega-
tive CT.130–132 CSF characteristics of SAH include an elevated opening pressure,
presence of erythrocytes or red blood cells, and xanthochromia. CSF should be visu-
ally inspected for the presence of xanthochromia, a term that refers to the yellow
aspect of the CSF attributable to the formation of bilirubin from the breakdown of
hemoglobin in the CSF.133
Special consideration should be given to the use of spectrophotometry in CSF anal-
ysis for the detection of bilirubin. The use of this technique is strongly advocated in the
United Kingdom, where the rate of visual assessment of the cerebrospinal fluid fell to

Fig. 3. SAH in the left sylvian fissure, sulci of the left hemisphere and along the left and
central aspect of the suprasellar cistern, left ambient cistern, and interpenduncular cistern.
784 Caceres & Goldstein

Fig. 4. 3-D reconstruction CTA on the same patient as in Fig. 3. An aneurysmal sac is appre-
ciated at the distal M1 segment of the left middle cerebral artery.

6%, whereas the use of spectrophotometry rose to 94% in recent years.134 This
method has been shown to have approximately 100% sensitivity for the detection
of bilirubin in patients with SAH but with low specificity.135,136 In the United States,
however, the majority of centers use visual inspection instead.137 Some investigators
recommend spectrophotometry, if available, in those cases where visual inspection
yields doubtful results.138

Digital subtraction angiography

Digital subtraction angiography allows for direct visualization of the cerebral vascula-
ture and remains the gold standard for detecting aneurysms. This diagnostic tool
requires a dedicated neurointerventional team and provides an opportunity for thera-
peutic interventions as well as diagnosis.

MRI
MRI is rarely used to diagnose SAH in the ED because availability is limited, and logis-
tical barriers to its use are much higher than with CT. Blood is not easily detectable in
T1-weighted and T2-weighted MRI sequences in the acute setting, likely because the
generation of deoxyhemoglobin with paramagnetic properties is delayed in the
subarachnoid space.139 The sensitivity of fluid-attenuated inversion recovery
sequences, however, is comparable to that of the CT in the acute phase of an SAH
and potentially superior in the subacute phase.140,141

Emergency Management
Airway management
The initial management of an SAH does not differ from other medical emergencies,
and airway management is similar to that described previously for ICH.

Neurologic examination
During the initial evaluation, a neurologic examination should be performed and docu-
mented. Clinical grading scales that mark the severity of SAH include the Hunt and
 Intracranial Hemorrhage 785

Hess scale (Table 5) and the WFNS grading scale (see Table 4). The Hunt and Hess
scale was originally designed to evaluate the operative risk of patients and to aid at
deciding the best timing for neurosurgical intervention,142 but it is now widely known
and accepted as a predictor of outcome. It is based on the level of severity of clinical
signs with a correlation with poor outcome with a higher grade. The WFNS grading
scale uses the GCS score and groups them into 5 grades and also takes into account
the presence of a motor neurologic deficit.143
Medical Management
Blood pressure management
When considering an optimal BP goal, an appropriate balance should be maintained.
Hypotension may theoretically increase the risk of ischemia, whereas elevated BP rai-
ses the concern for aneurysmal rupture and rebleeding. Current guidelines recom-
mend that hypotension should be avoided and that treatment of HTN should be
initiated until the aneurysm is secure only with extreme BP values when the MAP is
greater than 110 mm Hg, aiming at maintaining a good CPP. The recommended
agents to lower BP are nicardipine, labetalol, and esmolol.129,144
Seizure prophylaxis
To date, no randomized controlled trial has evaluated the benefits of the prophylactic
use of AEDs in patients with SAH. The incidence of seizure varies extensively in the
literature.145 Risk factors for the development of onset seizures include poor Hunt
and Hess score, acute hydrocephalus, cerebral ischemia, and large volume of
subarachnoid blood.129,146,147
Nonconvulsive seizures and nonconvulsive status epilepticus may occur after SAH,
leading clinicians to recommend continuous electroencephalography monitoring in
patients with poor Hunt and Hess scores.148 Current guidelines recommend consid-
ering the use of routine AEDs, especially in patients at higher risk, and using an alter-
native to phenytoin, which has been linked to a poor prognosis.129 Commonly used
agents include levetiracetam, valproate, and fosphenytoin (it is unclear whether this
shares the same possible negative effects as phenytoin).
Glycemic control
Both elevated and low glucose levels are associated with worse outcome after SAH.
Hypoglycemia is associated with vasospasm, infarction, and more disability at 3
months. Hyperglycemia on admission and during hospitalization is also associated
with poor outcome and short-term mortality.149–151 Although a specific target glucose
level has not been established, it is currently recommended to avoid hypoglycemia
(serum glucose <80 mg/dL) and maintain maximum values below 200 mg/dL.129

Table 5
Hunt and Hess grading scale

Grade Criteria
1 Asymptomatic or minimal headache and slight nuchal rigidity
2 Moderate to severe headache, nuchalrigidity, no neurologic deficit other than
cranial nerve palsy
3 Drowsiness, confusion, or mild focal neurologic deficit
4 Stupor, moderate to severe hemiparesis, possibly early decerebrate rigidity
5 Deep coma, decerebrate rigidity

Data from Hunt WE, Hess RM. Surgical risk as related to time of intervention in the repair of intra-
cranial aneurysms. J Neurosurg 1968;28(1):14–20.
786 Caceres & Goldstein

Temperature
Fever is common after SAH. Fever at admission and its presence during hospitaliza-
tion are associated with poor outcome.152 A possible infectious etiology should always
be investigated, although this is uncommon during initial presentation. Medical and
physical interventions can be used as therapeutic measures to reduce fever.
Currently, it is recommended to initiate therapy with antipyretic agents, such as acet-
aminophen, when fever is present.129 Physical surface or intravascular cooling
devices should be used only when antipyretics fail, and close monitoring and treat-
ment of shivering should be started.129

Vasospasm and Delayed Cerebral Ischemia

Vasospasm and delayed cerebral ischemia are deadly complications of SAH associ-
ated with poor outcome. Angiographic vasospasm occurs in up to 70% of cases.153
Symptomatic vasospasm, associated with new focal neurologic findings and/or dete-
rioration in the level of consciousness, occurs in approximately 30% of cases.154
Delayed cerebral ischemia can occur days after the index SAH and can lead to neuro-
logic deterioration and focal neurologic deficits.155 One preventive measure is the use
of oral nimodipine (60 mg by mouth or nasogastric tube every 4 hours for 21 days) and
should be initiated soon after diagnosis of SAH.156 Once vasospasm occurs, a range
of medical and interventional therapies is available to maintain adequate cerebral
perfusion.129 One recognized therapy is the triple-H therapy, characterized by hyper-
volemia through volume expansion, HTN with BP augmentation, and hemodilution
aimed at reducing blood viscosity.157 Currently, the Neurocritical Care Society recom-
mends that euvolemia be pursued and that the routine use of hemodilution should be
reserved for cases of erythrocythemia.129 For BP augmentation, a stepwise approach
is recommended and an SBP goal of greater than 160 mm Hg or an MAP greater than
120 mm Hg is a reasonable approach.129,158

Aneurysm Repair
Patients with SAH require emergency neurosurgical and/or endovascular consulta-
tion. There are currently at least 2 options for the acute treatment of a ruptured aneu-
rysm: endovascular coiling or surgical clipping. Treatment of a recently ruptured
aneurysm reduces the rate of rebleeding, and the benefit is related to the time to treat-
ment initiation.159 Current guidelines recommend that surgical clipping or endovascu-
lar coiling should be performed to reduce the rate of rebleeding after aneurysmal SAH,
and these procedures should be performed early in the disease course.129,144
The selection of the most appropriate intervention depends on a range of character-
istics, including age, clinical status, and medical comorbidities. Aneurysm character-
istics, such as location, shape, and size, are taken into consideration as well,
highlighting the value of a specialized multidisciplinary group to provide care and deci-
sion making. Some expert consensus groups recommend that SAH be preferentially
managed at high-volume centers (defined as those centers with greater than 60 cases
of SAH per year).129

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