Ebook Textbook of neurointensive care (2/E): Part 2

Aneurysmal Subarachnoid
Hemorrhage: Evidence-Based
Medicine, Diagnosis, Treatment,
and Complications

24

Matthew M. Kimball, Gregory J. Velat, J.D. Mocco,
and Brian L. Hoh

Contents

Abstract

Introduction .................................................................................. 541
Natural History of Aneurysmal SAH ......................................... 542
Diagnosis and Initial Management .............................................
Presentation .....................................................................................
Initial Evaluation and Imaging........................................................
Contrast Prophylaxis .......................................................................

542
542
542
545

Initial Stabilization and Management........................................
Antifibrinolytics ..............................................................................
Seizures ..........................................................................................
Hydrocephalus ................................................................................

546
547
547
548

Treatment Methods for Ruptured Cerebral Aneurysms.......... 548
Surgical Treatment Options ............................................................ 548
Endovascular Treatment.................................................................. 550
Cerebral Vasospasm and SAH .................................................... 551
Modalities for Identifying Cerebral Vasospasm ............................. 551
Vasospasm Prophylaxis and Management ...................................... 552
Medical Complications of Subarachnoid Hemorrhage ............
Cardiac and Pulmonary Complications ..........................................
Anemia and Transfusion .................................................................
Hyponatremia..................................................................................

556
556
557
558

Aneurysmal subarachnoid hemorrhage is a devastating
condition with high mortality and morbidity rates for
those that survive the initial hemorrhage. There has been
significant research on aneurysmal subarachnoid hemorrhage to better understand how we can diagnose, treat,
and manage patients with this disease. Cerebral vasospasm accounts for the majority of morbidity, mortality,
and long-term disability in these patients, and a large
volume of literature is dedicated to preventing and treating vasospasm. This chapter presents a simplified, evidence-based review of the literature about the modes of
diagnosis, medical and surgical management, and treatment options of patients with aneurysmal subarachnoid
hemorrhage and cerebral vasospasm.

Keywords

Cerebral aneurysm • Cerebral vasospasm • Evidencebased treatment • Hydrocephalus • Subarachnoid
hemorrhage

References ..................................................................................... 559

Introduction
M.M. Kimball, MD • B.L. Hoh, MD, FACS, FAHA, FAANS (*)
Department of Neurological Surgery,
University of Florida College of Medicine,
100265, Gainesville, FL 32610, USA
e-mail: ;

G.J. Velat, MD
Department of Neurosurgery,
Lee Memorial Hospital, Fort Myers, FL 33901, USA
e-mail:
J.D. Mocco, MD, MS, FAANS, FAHA
Department of Neurosurgery,
Vanderbilt University Medical Center,
1161 21st Ave S, RM T4224 MCN, Nashville, TN 37232, USA
e-mail:
A.J. Layon et al. (eds.), Textbook of Neurointensive Care,
DOI 10.1007/978-1-4471-5226-2_24, © Springer-Verlag London 2013

Aneurysmal subarachnoid hemorrhage (SAH) is a devastating condition accounting for about 5 % of all strokes,
affecting about 30,000 people in the United States every
year [1, 2]. The annual prevalence of aneurysmal SAH is
likely higher than 30,000 due to misdiagnosis and those

who do not receive medical care. The incidence of aneurysmal SAH varies around the world and has been reported
anywhere from 2 to 23 per 100,000 [3, 4]. Mortality rates
range from 32 to 67 % [5] with a significant degree of morbidity among those who survive the initial hemorrhage
[6, 7]. Recent data have shown that there may be a declining mortality rate after aneurysmal SAH with more recent
treatment modalities [8]. However, despite many advancements such as endovascular therapy for the treatment of
541


542

aneurysms and the ability to better diagnose and treat cerebral vasospasm, morbidity remains high.
Aneurysmal SAH typically affects adults in the fifth to
seventh decades of life and is about 1.6 times more common
in females than in males [9, 10]. Some genetic syndromes
have a higher risk of aneurysm formation and hemorrhage,
such as polycystic kidney disease [11] and Ehlers-Danlos
[12] syndrome. Familial intracranial aneurysm syndrome is
when two or more first- through third-degree relatives are
found to have intracranial aneurysms. Those who have this
syndrome are more inclined to harbor multiple intracranial
aneurysms and experience aneurysmal SAH at a younger age
[13]. Additional risk factors for developing aneurysmal SAH
include hypertension, smoking history, and alcohol abuse all
of which have been validated on multivariate analyses
[14, 15]. Cocaine use and other sympathomimetics have also
been shown to increase risk of SAH, particularly in younger
patients with SAH [16].

M.M. Kimball et al.

Institutional factors included availability of endovascular
services, volume of SAH patients treated at a given institution, and the type of facility in which the patient is first
evaluated.
Rebleeding after the initial hemorrhage carries a very
high mortality rate of approximately 70 % and is highest in
the first 24–48 h [25]. The International Cooperative Study
on the Timing of Intracranial Aneurysm Surgery [26] found
that patients who underwent aneurysm treatment in <72 h
had a 5.6 % rebleed rate with 73 % of those occurring in the
first 24 h. Overall, they reported a rate of 4.1 % for the first
24 h and 1 % per day for the first two weeks. More recent
studies have shown that rebleeding may be more common in
the first 2–12 h [27, 28]. Current literature supports early
securing of ruptured aneurysms through either microsurgical
or endovascular means to prevent rebleeding and improve
overall patient outcomes.

Diagnosis and Initial Management
Natural History of Aneurysmal SAH
Presentation
It is estimated that approximately 15 % of patients die at the
time of hemorrhage before receiving medical care. About
30 % of those that survive the initial hemorrhage have moderate to severe disability [5], and about two-thirds who survive to undergo successful aneurysm treatment never regain
their baseline quality of life [5]. The overall mortality rate is
about 45 %, with most deaths occurring within the first few
days following rupture. In one series, the 30-day mortality
rate was 46 % [17], and in another study over half of the
patients died within 14 days of hemorrhage [18]. For those
that survive the initial hemorrhage, approximately 8 % will
die from progressive deterioration [19]. Rebleeding before

aneurysm treatment remains the major cause of morbidity
and mortality following the initial hemorrhage, supporting
the need for early treatment (within 72 h) of aneurysm rupture. For those who survive to undergo treatment, cerebral
vasospasm accounts for the majority of morbidity and mortality. Angiographic vasospasm occurs in 30–70 % of
patients between the fifth and fourteenth days following
SAH [20, 21]. Approximately 50 % of patients with angiographic vasospasm will develop delayed ischemic neurologic deficits (DINDS), and 15–20 % of these patients will
suffer major stroke or death despite intervention [22, 23].
Bederson and coworkers [24] analyzed patient, aneurysm,
and institutional factors on clinical outcomes following
aneurysmal SAH. They included patient factors as severity/
grade of initial hemorrhage, age, sex, time to treatment, and
medical comorbidities including hypertension, atrial fibrillation, congestive heart failure, coronary artery disease, and
renal disease. Aneurysm factors included size and location.

The classic presentation of an awake patient with an aneurysmal SAH is the complaint of the worst headache of their life.
The headache may also be associated with nausea, vomiting,
nuchal rigidity, photophobia, a brief loss of consciousness,
cranial neuropathy, or other focal neurologic deficits.
Although there has been a drastic improvement in diagnosis
by primary care and emergency medical providers, there is
still a reported misdiagnosis rate of about 12 %, in which the
most common diagnostic error was failure to obtain a noncontrast computed tomographic (CT) scan of the head [24].

Initial Evaluation and Imaging
A noncontrasted head CT is the most important tool for diagnosis of a SAH (Fig. 24.1a). A CT scan is 98–100 % sensitive for the diagnosis of SAH if done within 12 h of
hemorrhage. The sensitivity decreases to about 93 % at 24 h
and 85 % at 6 days after SAH [29, 30]. In a patient with a
known aneurysm and a negative head CT or a patient with a
concerning recent history for SAH and a negative head CT,
lumbar puncture (LP) can be extremely valuable for diagnosing aneurysmal SAH. It is extremely important that the person performing the lumbar puncture understands how to

collect and handle the cerebrospinal fluid (CSF), order the
correct labs, and effectively communicate with the laboratory personnel to achieve accurate test results. It is important
to know the relationship between the timing of the LP and
onset of symptoms, to be able to interpret the results. Lumbar


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Aneurysmal Subarachnoid Hemorrhage: Evidence-Based Medicine, Diagnosis, Treatment, and Complications

543

a

b

c
Fig. 24.1 (a–e) Illustrative case. 78-year-old woman with Hunt-Hess
grade 3, Fisher score 3 subarachnoid hemorrhage. (a) Noncontrast head
computed tomographic (CT) scan demonstrates Fisher score 3
subarachnoid hemorrhage with hydrocephalus. A right frontal ventriculostomy drain catheter has been placed. (b) Maximal intensity projection (MIP) reconstructions of CT angiography (axial on left, sagittal on
right) demonstrate a ruptured left posterior communicating artery
aneurysm with daughter sac (arrowheads). (c) Anteroposterior (AP,
left) and lateral (right) projection cerebral angiography demonstrates a

ruptured left posterior communicating artery aneurysm with daughter
sac (arrowheads). A dime is superimposed on the lateral projection for
measurement calibration. (d) Endovascular balloon-assisted coiling of
the ruptured left posterior communicating aneurysm is demonstrated on
AP (left) and lateral (right) projection roadmap cerebral angiography

(inflated balloon, arrows; coiling, arrowheads). (e) Completed coil
occlusion of the left posterior communicating artery aneurysm is
demonstrated on AP (left) and lateral (right) projection cerebral
angiography


544

M.M. Kimball et al.

Fig. 24.1 (continued)

d

e

puncture results in SAH have been well studied and are the
most sensitive test for SAH [31, 32].
Lumbar puncture should be performed carefully, as some
believe that by removing a large volume of CSF, the transmural pressure gradient across the aneurysm dome may increase
leading to hemorrhage. Measuring an opening pressure may
be helpful, particularly in the setting of hydrocephalus, but is
not diagnostic of aneurysmal SAH. Occasionally, patients
with a remote history of SAH may present with symptoms of
hydrocephalus. It is necessary to be able to differentiate
between a traumatic tap and a true SAH [33] (Table 24.1).
The most critical data show the comparison of the red blood
cell (RBC) count in the first and last tubes, and the presence
of xanthochromia in the supernatant fluid. Cerebrospinal
fluid in SAH patients is typically bloody or grossly xanthochromic with a yellow or pink color but does not typically

clot when collected. Traumatic taps commonly consist of
gross blood and clot during collection. The RBC count should
remain fairly consistent between the first and last tube, where
it will likely decline with a traumatic tap. After the CSF is
collected, it is spun down and a supernatant fluid is collected
and tested for xanthochromia, which is a discoloration of the
CSF due to heme breakdown products from RBCs. This is
the most reliable means of differentiating aneurysmal SAH
from a traumatic tap. Although gross visual inspection can be
helpful, spectrophotometry is much more accurate. Timing of
LP and symptoms are very important. Xanthochromia does
not appear until 2–4 h after SAH but is present in 100 % of
patients at 12 h and remains in the CSF in about 70 % of
patients at 3 weeks but drops off significantly between 3 and
4 weeks. If a patient has a normal noncontrasted head CT and
CSF profile, aneurysmal SAH is essentially ruled out.


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Table 24.1 CSF results in SAH versus traumatic LP
CSF feature
Red blood cell count (RBC)
Fluid appearance (gross)
Supernatant appearance (spun)

Clotting
WBC/RBC ratio
Opening pressure
Protein

SAH
Usually >100,000 RBC/mm3
(little change between first and last tube)
Xanthochromia (yellow/pink)
Xanthochromia
Usually does not clot
Slight leukocytosis
Commonly elevated
Commonly elevated

Magnetic resonance imaging is currently of little diagnostic value for acute aneurysmal SAH due to poor sensitivity to
detect methemoglobin molecules in the first 24–48 h following rupture. Patient compliance, duration of time needed to
obtain the scan, and increased cost compared to CT scanning
have relegated MR imaging in the diagnosis of aneurysmal
SAH. Magnetic resonance angiography (MRA) may be used
in patients with renal insufficiency, acute renal failure, or
pregnant patients to diagnose intracranial aneurysms with
reduced sensitivity and specificity compared to CT angiography (CTA). MRA sensitivity ranges from 85 to 100 % for
aneurysms >5 mm but drops to approximately 56 % for
aneurysms ≤5 mm [34, 35]. MRI and MRA may be helpful
when looking for other causes of SAH such as cervical spinal arteriovenous malformations that may be missed by conventional CTA.
The most useful noninvasive imaging modality in acute
SAH is CTA (Fig. 24.1b). It can be obtained quickly, provides excellent three-dimensional reconstructions, shows
relationship of aneurysms to bony landmarks, may show
thrombus or calcification within the aneurysm, is noninvasive, and has a high sensitivity and specificity. Sensitivity of

CTA for aneurysms ranges from 95 to 100 % for aneurysms ≥5 mm but drops off to 64–83 % for aneurysms ≤5 mm
[36–38]. CTA sensitivity diminishes with small aneurysms,
increased blood products, and may vary in accordance with
experience of the interpreting neuroradiologist. Potential
disadvantages of CTA include the inability to adjust the contrast dose and/or concentration for patients at risk of renal
dysfunction, artifact from previous aneurysm clips or
embolic material may obstruct aneurysm diagnosis, and
small distal vessels may not be well visualized. Currently,
CTA is the diagnostic imaging study of choice for initial
detection of intracranial aneurysms.
Cerebral angiography, the traditional gold standard diagnostic test for intracranial aneurysms, is typically performed
if CT angiography fails to reveal a potential bleeding source.
Cerebral angiography holds many advantages over other
diagnostic imaging techniques. First, it allows for methodical evaluation of the intracranial vasculature via selective
injection of intracranial arteries. PA and lateral projections
are obtained simultaneously to better characterize the exact

Traumatic tap
RBC should decrease between first and last
tube
Bloody
Clear
Typically clots
Same as peripheral blood
Commonly normal
May be elevated slightly

location and morphology of intracranial aneurysms
(Fig. 24.1c). Three-dimensional reconstructions can be readily obtained. In addition, cerebral vasculature surrounding an
intracranial aneurysm is delineated. Endovascular intervention may be pursued at the time of cerebral angiography,

effectively streamlining aneurysm treatment. Contrast load
can also be altered, which may benefit patients with renal
insufficiency. Despite the improved sensitivity of cerebral
angiography for the diagnosis of intracranial aneurysms or
other vascular malformation causing SAH, in about 20–25 %
a source of hemorrhage will not be found. Many centers
repeat a diagnostic cerebral angiogram 1 week after the initial angiogram to evaluate for a small aneurysm that was
unable to be visualized on the initial study. In about 1–2 % of
patients, an aneurysm is found after repeat angiogram [39]. It
is controversial whether the small percentage of aneurysms
found on repeat angiography warrants a repeat angiogram on
all patients with a single negative diagnostic cerebral angiogram. We feel that the small morbidity of a diagnostic cerebral angiogram of about 1–2 % versus the morbidity and
mortality of a re-ruptured undiagnosed aneurysm warrants a
repeat angiogram.

Contrast Prophylaxis
The number of diagnostic and therapeutic spinal and cerebral
angiograms has gone up exponentially in the last 20 years
and therefore the use of iodinated contrast media. Although
newer and safer contrast media have been developed and
used over recent years, we need to understand the risks of
using these agents. The majority of the literature on these
agents comes from the cardiology literature where there is a
much higher patient population to study. Low-osmolality
agents have been in use since the 1980s and have had a direct
reduction in the pain associated with administration as well
as adverse events. These agents have been proven to be safe
but are associated with a small percentage of adverse reactions ranging from rash and flushing to angioedema, vasomotor collapse, and death. The risk for adverse reactions
increases with higher osmolarity and ionicity. The risk for all
adverse reactions ranges from 4 to 12 % with ionic agents

546

compared to 1–3 % with nonionic agents [40]. The risk for
severe reactions such as anaphylaxis and vasomotor collapse
was significantly lower for low-osmolality agents 0.03 %
compared with 0.16 % for high-osmolality agents [41]. The
strongest risk factors for predicting an adverse reaction to
contrast are a previous history of contrast reaction and atopic
conditions such as asthma. A previous history of a contrast
reaction gives a 17–35 % risk of future reaction [42]. Asthma
increases the risk of reaction by approximately six times the
general population [43]. Other risk factors reported for contrast reactions include underlying heart disease, renal disease, diabetes mellitus, myeloma, sickle cell disease,
polycythemia, food or medication allergies, hay fever, nonsteroidal anti-inflammatory drug use, beta-blocker use, age
greater than 60, and female gender [44]. There has been a
long debated argument as to risk of a contrast reaction in a
patient with a known shellfish allergy. There has never been
a reported case of shellfish allergy where iodine was implicated, and the reaction to radiocontrast media has never been
proven to be related in any way to the iodine content in a
preparation. Routine premedication for contrast reaction
prior to contrast is not supported by the evidence currently
available in the literature for those with shellfish allergy. Two
major prophylaxis regimens are approved by the American
College of Radiology and include:
Pretreatment Protocol 1:
(a) Prednisone 50 mg orally 13, 7, and 1 h prior to
procedure
(b) Diphenhydramine 25–50 mg intravenously, intramuscularly, or orally 1 h prior to procedure
(c) Nonionic low-osmolality contrast medium

Pretreatment Protocol 2:
(a) Methylprednisolone 32 mg orally 12 and 2 h prior to
procedure
(b) Diphenhydramine 25–50 mg intravenously, intramuscularly, or orally 1 h prior to procedure
(c) Nonionic low-osmolality contrast medium
The use of these preventative protocols has reduced the
incidence of severe reactions and should be used in the
appropriate populations. In the instance that waiting the
12–13 h is not reasonable for diagnosis or treatment by CTA
or cerebral angiogram, a single dose of 100 mg of hydrocortisone sodium succinate can be given intravenously at the
time of the procedure.

Initial Stabilization and Management
The patient should be transferred out of the emergency medical setting to a neurosurgical ICU setting as soon as possible.
The admission Hunt-Hess grade (Table 24.2), Fisher score
(Table 24.3), and World Federation of Neurologic Surgeons
(WFNS) grade (Table 24.4) should also be reported, as it

M.M. Kimball et al.
Table 24.2 Hunt-Hess classification
Grade
1
2
3
4
5

Description
Asymptomatic or minimal headache and slight nuchal
rigidity

Moderate to severe headache, nuchal rigidity, no
neurologic deficit except cranial nerve palsy
Drowsy, minimal neurologic deficit
Stuporous, moderate to severe hemiparesis, early
decerebrate rigidity
Deep coma, decerebrate rigidity, moribund

Reproduced with permission from Hunt and Hess [45]

Table 24.3 Fisher score
Fisher grade
1
2
3
4

Appearance of blood on CT scan
No hemorrhage evident
Subarachnoid hemorrhage less than 1 mm thick
Subarachnoid hemorrhage more than 1 mm thick
Subarachnoid hemorrhage of any thickness with
intraventricular hemorrhage or intraparenchymal
hemorrhage

Modified with permission from Fisher et al. [46]

Table 24.4 World Federation of Neurologic Surgeons (WFNS) grade
WFNS grade
0
1

2
3
4
5

Glasgow coma score

Major focal deficit

15
13–14
13–14
7–12
3–6

No
No
Yes
Yes or no
Yes or no

Reproduced with permission from Drake [47]

may aid treatment, prognosis, and risk of vasospasm. The
Airway management, breathing, and hemodynamic stability
are the first priority. All of these should be managed with the
understanding that manipulation of the airway may induce
gag or cough reflexes, elevations in PCO2, and intubation
may elevate blood pressure, acutely placing the patient at
high risk for rebleeding. Preoxygenation should be done

prior to intubation. The gag and cough reflex, and reflex
cardiac dysrhythmias can be avoided by appropriate pharmacologic agents. Although bed rest and a low-stimulation
environment have been accepted as common management
for an unsecured aneurysm, there are no data to support that
it lowers the risk of early rebleeding; however, it causes
no harm to the patient and should probably be followed.
There is a large amount of literature in regard to treatment
of hypertension in the acute period for an unsecured aneurysm; however, no well-controlled studies have been done
to show that strict blood pressure control has any effect on
rebleeding rates. A retrospective study has shown that there
appears to be a lower risk of rebleeding in those treated with


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Aneurysmal Subarachnoid Hemorrhage: Evidence-Based Medicine, Diagnosis, Treatment, and Complications

547

antihypertensive medications, but in this study those treated
had higher blood pressures than those not treated, and there
did not appear to be a correlation with a lower blood pressure [48]. Another study had stated that rebleeding may be
related to greater variations in blood pressure and not an
absolute value [49]. A specific goal systolic blood pressure
(SBP) remains controversial and variable, but most would
agree that a SBP goal <150 mmHg would be safe. When
treating elevated SBP, short-acting agents given by continuous infusion are ideal as they can be titrated easily to prevent large fluctuations. Beta-blockers such as labetalol and
esmolol and calcium channel blockers such as nicardipine
may be used safely with minimal side effects and easy to
titrate. Hydralazine can be given intravenously as needed for

patients with bradycardia. Sodium nitroprusside should be
avoided or used for less than 24 h as it can raise intracranial
pressure by direct vasodilation, having greater effect on the
arterial than the venous system. It can also cause toxicity by
its breakdown products thiocyanate and cyanide. It should
be used for acute management until other medications can
be titrated to control blood pressure. Blood pressure control should be balanced between preventing rebleeding and
hypotensive episodes that reduce cerebral perfusion pressure
(CPP) and risk of ischemic events.

cohort trials. A randomized trial by Hillman [52] included
505 patients of which 254 were treated with tranexamic acid
within 48 h of SAH. A significant reduction in rebleeding
from 10.8 to 2.4 % was seen among the two groups and a
nonsignificant 19 % reduction in poor outcome, and a 4 %
increase in good outcome was also noted. A cohort-controlled
study by Starke [53] consisted of 72 patients who received
EACA on admission that was continued for <72 h, compared
to 175 patients that did not receive an antifibrinolytic. A significant reduction in rebleeding was seen in the EACAtreated group 2.7 % versus 11.4 % in the non-treated group.
No significant difference was seen between ischemic complications between the two groups; however, an 8-fold increase
in deep venous thrombosis (DVT) was found in the EACAtreated group without a difference in pulmonary embolism
(PE) incidence. A retrospective review by Harrigan [54] of
356 patients compared to historical controls and determined
short-term administration of EACA is associated with rates
of rehemorrhage, ischemic stroke, and symptomatic vasospasm that compare favorably with historical controls.
Overall, it appears that there is significant decrease in the
incidence of early rehemorrhage with early use of antifibrinolytics which should be discontinued in less than 72 h to
decrease the risk of embolic and ischemic complications.

Antifibrinolytics

Seizures

The use of antifibrinolytics for the prevention of early rehemorrhage has been studied since the late 1960s and early
1970s. Early studies showed similar results which included a
significant reduction in the incidence of early rebleeding;
however, this was offset by an increased risk of cerebral
infarction and DINDs. The two major medications used are
tranexamic acid and epsilon-aminocaproic acid (EACA). In
1981, Torner [50] reported results from the Cooperative
Aneurysm Study in regards to a randomized, double-blinded,
placebo-controlled trial using tranexamic acid use for
patients after SAH. A slightly greater than 60 % reduction
was seen in rebleeding in the treatment group, but there was
a significant increased risk of cerebral infarction in the treatment group. In 1984, Kassel [51] gave a report from the
Cooperative Aneurysm Study, which showed a 40 % reduction in rebleeding among those patients receiving an antifibrinolytic but a 43 % increase in focal neurologic deficits.
Because of the decrease in rebleeding rates but the increase
in neurologic deficits, it was believed that, if the antifibrinolytic was used for a short time period until securing of the
aneurysm and stopped before the vasospasm period, the
increased ischemic complications might decrease.
Since 2002, there have been 3 major studies comparing
the use of short-term antifibrinolytics during SAH to prevent
rebleeding: 1 randomized controlled trial and 2 retrospective

There has always been an association between SAH and seizures; however, the true incidence and its effect on clinical
outcome are debated. In a study by Lin [55], 217 patients
with aneurysmal SAH were reviewed for incidence and timing of seizures and followed for 2 years. Overall, 21 % of all
patients experienced one seizure, with 37 % of those being at
onset of SAH, 11 % preoperative seizures, and 46 % had at
least one seizure after the first week. In total, 6.9 % of the

217 patients developed late epilepsy, but only 3.8 % of
patients who had a seizure during the hospitalization developed late epilepsy.
There has been a significant amount of debate in regards
to whether seizures associated with SAH have an effect on
outcome. Antiepileptic drugs (AEDs) have side effects as
well, and some argue that the medications themselves can
have an effect on outcome after SAH. A study [56] using
the Nationwide Inpatient Sample Database (NISD) reported
that generalized convulsive status epilepticus (GCSE) was
independently associated with higher in-hospital mortality,
longer hospital stays, and higher costs. Literature on nonconvulsive status epilepticus (NCSE) is poor, and the incidence is probably higher than reported. There have been
some retrospective studies showing a relationship between
phenytoin use in SAH and poor outcome, but because of the
retrospective nature and difficulty in interpretation of the


548

data, no recommendations can be made at this time. A study
by Chumnanvej [57] reported that 3 days of phenytoin after
SAH was adequate for seizure prophylaxis. They compared
79 patients who had previously undergone multi-week phenytoin prophylaxis after SAH versus 370 patients in which
only 3 days of phenytoin were given and then discontinued.
There was a significant reduction in phenytoin-related complications such as hypersensitivity reactions, but the percentage of patients who had seizures, short or long term, did
not change significantly between the two groups. Although
this study is not a prospective randomized trial, it may be
beneficial to provide a 3-day regimen of phenytoin prophylaxis after SAH to minimize medication side effects such as
hypersensitivity reactions, cognitive effects, and interaction
with other medications while providing seizure prophylaxis.

Hydrocephalus
Acute hydrocephalus occurs in 15–87 % [58–60] of patients
that present with aneurysmal SAH. Of those patients, however, only 8.9–48 % [58–60] develop chronic shuntdependent hydrocephalus. The management of acute
hydrocephalus secondary to aneurysmal SAH is usually
managed by external ventricular drainage (EVD) or lumbar
drainage (LD). Treatment of acute hydrocephalus with an
EVD is associated with neurologic improvement [61–63].
There has been some concern about the risk of rebleeding after
placement of an EVD. Three retrospective case series have
evaluated this topic. One study found that there was an
increased risk of rebleeding with EVD placement [64], and the
other two found no increased risk [65, 66]. Lumbar drainage
for the treatment of SAH-associated hydrocephalus has only
been evaluated in retrospective studies and has been found to
be safe and not increase the risk for rebleeding [67–70]. There
has been suggestion that lumbar drainage decreases the incidence of vasospasm but has only been studied in retrospective series [68]. Serial lumbar puncture for management of
SAH-associated hydrocephalus has also been described as
safe and not increasing the risk of rebleeding, but only in
small retrospective series [71].
The management of chronic hydrocephalus associated
with aneurysmal SAH is usually managed by ventricular shunt
placement. External ventricular drainage weaning can be done
in a variety of ways. A small single-center prospective randomized control trial studied a method for determining which
patients would require permanent ventricular shunt placement
[72]. Forty-one patients were randomized to rapid EVD weaning (<24 h), and 40 patients were randomized to gradual EVD
weaning (96 h weaning period). There was no difference in
rate of shunt placement between the two groups, but the gradual wean group had 2.8 more days in the intensive care unit
(p = 0.0002) and 2.4 more days in the hospital (p = 0.031).

M.M. Kimball et al.

Several factors have been studied to attempt to identify
factors predictive of SAH-associated shunt-dependent hydrocephalus. One factor that has been studied is whether clipping
versus coiling affects the incidence of shunting. A meta-analysis [60] of five non-randomized with 1,718 patients (1,336
clipped, 382 coiled) studies showed that the rate of shunt
dependency was lower in the clipping group when compared
to the coiling group (p = 0.01); however, only one of the five
studies when evaluated independently showed a significant
difference [73]. Fenestration of the lamina terminalis has
been suggested to reduce the incidence of shunt-dependent
hydrocephalus. A meta-analysis of 11 non-randomized studies including 1,973 patients (975 fenestrated, 998 non-fenestrated) found no significant difference in shunt-dependent
hydrocephalus between the two groups [74].
Subarachnoid-associated acute hydrocephalus can safely
be managed by external ventricular drainage or lumbar
drainage. It may potentially improve the neurologic exam
and may slightly increase the risk of rebleeding. Although
the benefit of neurologic improvement has only been shown
in retrospective series, it has been consistently shown in
these studies, and the slight risk of rebleeding with placement is not greatly supported in the literature. Chronic
hydrocephalus from SAH can be treated with ventricular
shunt placement. Determination of shunt dependency by
weaning of EVDs within a <24-h period can be done safely
without increasing the rate of shunt placement. There is no
clear evidence that the modality of aneurysm treatment (clipping versus coiling) is associated with the development of
shunt-dependent hydrocephalus. It is unlikely that lamina
terminalis fenestration decreases the rate of shunt-dependent
hydrocephalus.

Treatment Methods for Ruptured Cerebral
Aneurysms

Two basic treatment options exist for ruptured cerebral aneurysms: open surgical clipping or wrapping and endovascular
coil embolization. Whether done from inside or outside of
the vessel, the goal is to exclude the aneurysm from the cerebral circulation. Ruptured aneurysms should ideally be
treated as early as possible, within the first 24 h, to prevent
rebleeding.

Surgical Treatment Options
Surgical treatment of aneurysms may involve clipping with
titanium clips, wrapping with synthetic substances, or ligation of the feeding vessel. Surgical treatment for ruptured
cerebral aneurysms is seated in a long history of courageous
and intelligent pioneers developing new ways to treat this


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Aneurysmal Subarachnoid Hemorrhage: Evidence-Based Medicine, Diagnosis, Treatment, and Complications

deadly pathology. Surgery for ruptured aneurysms first began
with what were considered “passive” strategies. Victor
Horsley was given credit for successfully treating the first
ruptured cerebral aneurysm in 1885 by ligating the ipsilateral
cervical carotid artery [75]. In 1931, Dott developed the
technique of reinforcing the aneurysm wall by wrapping it
with a piece of muscle [76]. Walter Dandy was credited in
1942 with the idea of trapping aneurysms to exclude them
from the circulation. All of these methods had high failure
rates, morbidity, and mortality. Eventually, a few brilliant
and dedicated surgeons came up with the idea that placing a
clip at the base of aneurysm while keeping the parent cerebral circulation patent may allow for definitive treatment. On
March 23, 1937, Walter Dandy placed a V-shaped silver clip

to the neck of an internal carotid artery aneurysm, and since
then this has become the gold standard for treatment of ruptured and unruptured aneurysms [77]. Multiple variations
and improvements have been made to the clip by many surgeons including Olivecrona, Schwartz, Mayfield, McFadden,
Kees, Drake, Heifetz, Sundt, Yasargil, Sugita, Spetzler, and
others [78].
Prior to 1970, carotid ligation was a common treatment
for ruptured intracranial aneurysms. Studies have shown
variable data in regard to rates of rebleeding and treatment
morbidity and mortality. In the Cooperative Aneurysm
Randomized Treatment Study [79], carotid ligation did not
lead to a significant improvement in mortality or rebleeding
in the acute period, compared with bed rest in the intent-totreat analysis. Only 67 % of those patients randomized to
carotid ligation actually received that therapy, and in that
group there was actually a lower mortality when compared to
the bed rest group, and no rebleeding occurred. Long-term
follow-up revealed a benefit for carotid ligation in reducing
rebleeding at 3 years and mortality at 5 years when compared to bed rest. A large retrospective study by Nishioka
[80], however, reported a rebleeding rate of 7.8 % after
carotid ligation with other associated complications of treatment. Overall, the treatment of ruptured aneurysms with
carotid ligation likely reduces the rate of rebleeding when
compared to bed rest alone, but the rate of complications
associated with treatment and rebleeding likely exceeds
those of surgical clipping.
Surgical clipping and endovascular embolization are preferred over carotid ligation for modern day treatment of ruptured cerebral aneurysms. Aneurysm location, morphology,
neck size, patient age, and medical comorbidities are all factors that may make a ruptured aneurysm more likely to be
coiled or surgically clipped. There has only been one large
trial comparing surgical and endovascular therapy for ruptured cerebral aneurysms. The ISAT [81] trial is a prospective, randomized study that selected 2,143 patients of 9,559
patients with aneurysmal SAH to be randomized to surgical
clipping or endovascular treatment, on the assumption that it

549

was agreed that their aneurysm could be treated by either
modality. There was no significant difference in mortality
rates at 1 year, 8.1 % in the endovascular group and 10.1 %
in the surgical group. Greater disability rates were seen in the
surgically treated group 21.6 % versus the endovascularly
treated group 15.6 %. This made the overall morbidity and
mortality of those treated surgically significantly higher than
those treated by endovascular means at 1 year follow-up. The
rebleeding rate was reported to be 2.9 % for coil embolization
and 0.9 % for clipping, and 139 patients who underwent coiling required further treatment compared to 31 patients that
were clipped. The confounding factor in many aneurysmal
SAH studies is what makes an aneurysm randomizable? In
this study they chose all patients with aneurysms in the anterior circulation, in awake, young patients, which is unclear if
that can be extrapolated to other groups.
Surgical clipping of aneurysms has been considered a
highly effective method for aneurysm treatment after SAH
with its low recanalization and rehemorrhage rates. It has
been shown that long-term rebleeding is reduced by either
carotid ligation or direct surgical clipping of the aneurysm
when compared to hypotension and bed rest [2], but there is
a higher rehemorrhage rate and complication rate with
carotid ligation when compared to direct surgical clipping.
In the Cooperative Study [82], all patients underwent surgical treatment for their ruptured aneurysms. Of the 453
patients, only nine patients (2 %) suffered rehemorrhage,
where four of these patients had multiple aneurysms. Sundt
[83] also reported a large study of 644 patients who underwent surgical clipping of ruptured aneurysms, with a 1.2 %
rate of rehemorrhage after clipping. In a more recent study
by David [84] in 1999, 160 aneurysms in 102 patients were

treated by surgical clipping and followed for mean of 4.4
years. They reported a complete obliteration rate of 91.8 %
on follow-up angiography, with a 0.5 % recurrence rate for
completely clipped aneurysms with no rehemorrhages. There
was a 1.9 % rehemorrhage rate for incompletely clipped
aneurysms with a small “dog-ear” residual. Incompletely
clipped aneurysms with a wide residual neck had a 19 %
recurrence and 3.8 % rehemorrhage rate. In total, they
reported a 2.9 % recurrence rate for all incompletely clipped
aneurysms with a total 1.5 % rehemorrhage rate.
Wrapping of aneurysms that are deemed unable to be
clipped has been described as a treatment modality with an
expected higher rehemorrhage rate than those that are clipped
or coiled. Small, older clinical studies have reported a smaller
rate of rehemorrhage than conservative management [85, 86].
A more recent long-term study reported an overall risk of
rehemorrhage after aneurysm wrapping or coating to be
33 % [87]. A long-term follow-up study of patients who
underwent surgical wrapping of ruptured aneurysms showed
a rehemorrhage rate of 11.7 % at 6 months and 17.8 % at 6
months to 10 years [88]. The rehemorrhage rate is similar to


550

rates of ruptured aneurysms treated by conservative management. The current data do not support the use of wrapping or
coating of ruptured cerebral aneurysms.

Endovascular Treatment
Endovascular management for treatment of cerebral aneurysms is a relatively young field despite the development of

cerebral angiography by Egas Moniz in 1927. Guido
Guglielmi [89] in 1991 first described the technique of
occluding aneurysms by an endovascular approach by using
platinum coils called Guglielmi detachable coils that were
detachable by applying a small current. The memory of the
coils allows them to fill the aneurysm and the coils induce
thrombosis. The aneurysm is packed until it is excluded from
the normal cerebral circulation. Technology in this field has
expanded much faster than our ability to study current
modalities. As endovascular methods have become more
available, the coil technology, delivery methods, and assistive techniques such as stent-assisted coiling or balloonassisted coiling (Fig. 24.1d, e) have become more common
allowing the morbidity to continue to decrease and ability to
coil aneurysms that were initially felt to be uncoilable.
There is great variability in the use of endovascular therapy for ruptured cerebral aneurysms. Some centers use it
as a first-line treatment and only clip if coiling cannot be
achieved. Other centers use endovascular treatment in critically ill patients or those with significant medical comorbidities that would otherwise be poor surgical candidates.
Some centers base their treatment modality on the CTA or
angiographic characteristics of the aneurysm. Despite the
variability in criteria for use, hospitals where endovascular techniques are available have been linked to improved
outcomes [90, 91].
It is difficult to study treatment modalities for SAH,
because it is often hard to separate the complications, morbidity, and mortality of the disease from the treatment. When
studying aneurysms, the two most important factors when
evaluating treatment modalities are the rebleeding rate and
recurrence or recanalization rate. Sluzewski [92] reported a
rebleeding rate of 1.4 % in 431 patients who underwent
endovascular coil embolization of ruptured cerebral aneurysms. Smaller studies have reported between a 0.9 and
2.9 % annual rate of rehemorrhage after endovascular embolization with increasing aneurysm size being an important
factor for rehemorrhage [24]. Degree of aneurysm occlusion
is also an important factor in risk of rehemorrhage. Murayama

[87] reported on their most recent 665 aneurysms in 558
patients treated by endovascular embolization. In small
aneurysms (4–10 mm) with small necks (≤4 mm), incomplete coiling occurred in 25.5 % with recurrence in 1.1 % of
completely coiled aneurysms and 21 % of incompletely

M.M. Kimball et al.

coiled aneurysms. In small aneurysms with wide necks
(>4 mm), incomplete coiling occurred in 59 %, with recurrence in 7.5 % of completely coiled aneurysms and 29.4 % of
incompletely coiled aneurysms. In large aneurysms (11–
25 mm), incomplete coiling occurred in 56 %, with recurrence in 30 % of completely coiled aneurysms and 44 % of
incompletely coiled aneurysms. Giant aneurysms (>25 mm)
had incomplete occlusion in 63 %, with recurrence in 42 %
of completely coiled aneurysms and 60 % in incompletely
coiled aneurysms. Despite the recurrence rates, most patients
with incomplete aneurysm obliteration do not rebleed.
Aneurysm recurrence is not uncommon after endovascular embolization, and recanalization can occur even in completely treated aneurysms. Close follow-up of patients treated
by endovascular means with formal cerebral angiography,
CTA, or MRA is extremely important, as additional embolization can be performed with low morbidity in an elective
environment. Timing for follow-up imaging is not defined
and can be variable depending upon whether the aneurysm
was found after SAH or incidentally, degree of occlusion,
size, and location. Derdeyn [88] followed 466 patients with
501 aneurysms for greater than 1 year after coil embolization
of cerebral aneurysms. They found recurrence in 33.6 % of
patients that occurred at a mean interval of 12.3 months after
the initial procedure. Frequent and long-term follow-up of
aneurysms treated by endovascular means are recommended
to identify recanalization and treat before SAH occurs.
Catheter cerebral angiography is the recommended modality

of choice for follow-up imaging in previously coiled or
clipped aneurysms. Although a small risk of permanent complications exists with diagnostic angiography, felt to be
<0.1 % [24], it allows the most precise view of the aneurysm
and neck and at the same time allows for retreatment if
needed. Coil and clip artifacts are often a problem with using
CTA and MRA for follow-up studies, although these are
noninvasive modalities.
No matter what treatment modality is chosen for ruptured
cerebral aneurysms, treatment should be done early to prevent rebleeding and to have a secured aneurysm prior to the
vasospasm window. Surgical clipping and endovascular coiling are both accepted treatment options for ruptured cerebral
aneurysms. Surgical wrapping or coating are not supported
by the data and may have similar rehemorrhage rates when
compared to conservative management, while placing the
patient at risk of the morbidity of a craniotomy after SAH.
Patient characteristics, medical comorbidities, aneurysm
location and morphology, and surgeon experience should all
be taken into account when deciding which modality should
be chosen. Currently, it is felt that the rate of incomplete
obliteration and recurrence is lower with surgical clipping
than with endovascular techniques; however, the morbidity
of surgical clipping and the long-term disability rates are
higher than endovascular treatment.


24

Aneurysmal Subarachnoid Hemorrhage: Evidence-Based Medicine, Diagnosis, Treatment, and Complications

Cerebral Vasospasm and SAH
After the aneurysm has been secured by surgical or endovascular means, the risk of rebleeding has generally been

removed; however, the treatment goals need to now be
focused on the prevention and treatment of cerebral vasospasm, delayed cerebral ischemia (DCI), and delayed ischemic neurologic deficits (DINDs). Cerebral vasospasm is a
delayed narrowing of the intracranial arteries from vasoconstriction leading to a decrease in cerebral blood flow, which
may lead to delayed cerebral ischemia (DCI) or delayed
ischemic neurologic deficits (DINDs) and cerebral infarction. There is a significant amount of variation in the literature about how cerebral vasospasm is identified, reported,
and defined. Some authors use vasospasm, DINDs, and DCI
synonymously, which makes interpretation of the literature
and the ability to compare treatment and prevention modalities very difficult. For the purposes if this chapter, vasospasm
is defined as the actual narrowing of intracranial arteries
diagnosed by cerebral angiography, CTA, or elevated velocities on transcranial dopplers (TCD), with the fact that there
is intra-observer error in interpreting these studies. In the setting of SAH, DCI and DINDs are typically secondary to
cerebral vasospasm and the reason they get used interchangeably; however, DCI is a clinical change in neurologic status
and may occur with or independently of angiographic evidence of vessel narrowing. The opposite may occur as well
where angiographic evidence of cerebral vasospasm occurs
in the absence of clinical decline. Delayed cerebral ischemia
may be reversible or may progress to DIND or cerebral
infarction on CT or MRI. The terms delayed cerebral ischemia (DCI) and delayed ischemic neurologic deficit (DIND)
are diagnoses of exclusion after all other causes of neurologic decline have been excluded including, seizures, hydrocephalus, hyponatremia, infection, iatrogenic from clipping
or coiling, or other metabolic causes. Delayed cerebral ischemia (DCI) and delayed ischemic neurologic deficits
(DINDs) will be defined as a neurologic decline that cannot
be explained by other means independently of angiographic
or TCD evidence of vasospasm. A third outcome measure
commonly used in SAH studies is the presence of cerebral
infarction on CT or MRI imaging of the brain. Cerebral
infarction is the irreversible loss of blood flow, which was
presumptively secondary to cerebral vasospasm in the setting of SAH. There has been a push to use cerebral infarct,
also known as “hypodensity on CT scan” in the literature, as
an independent outcome measure as it has been associated
with death or severe disability at 3 months, and is easily measurable in patients in a comatose state where neurologic
decline may be difficult to assess [93].

Cerebral vasospasm accounts for the majority of morbidity and mortality for patients who survive to undergo
treatment after aneurysmal SAH. Angiographic vasospasm

551

is observed in 30–70 % of patients after SAH and most commonly occurs between day 5 and 14, peaking around day 7
after the hemorrhage [20, 21]. It is estimated that about 50 %
of patients with angiographic vasospasm will develop DCI,
and about 15–20 % of these patients will develop DINDs,
stroke, or death despite aggressive therapy [22, 23]. Many
modalities for the prevention and treatment of cerebral
vasospasm, DCI and DINDs have been studied over the
years with variable results. This will be an evidence-based
synopsis for the diagnosis, management, and prevention of
cerebral vasospasm.

Modalities for Identifying Cerebral Vasospasm
Clinical evaluation of patients with symptomatic vasospasm
and DINDs are easy to identify because a measurable deficit
exists; however, a clinical evaluation may not be sensitive
enough to detect DCI as some patients may develop asymptomatic cerebral infarctions on CT or MRI. A prospective
study by Schmidt [94] studied 580 patients with aneurysmal
and non-aneurysmal SAH, where CT scans were done as
needed for clinical reasons. Asymptomatic infarcts were
noted on CT scans in 26 (4 %) patients and were noted to be
more common in patients in comatose states. After data analysis, those with cerebral infarcts were noted to have worse
modified Rankin Scores (mRS) at 3 months, which is consistently reported in the literature. Asymptomatic delayed cerebral infarction was also noted on CT scan in 4 % of patients
in a retrospective study of 143 aneurysmal SAH patients by
Rabinstein [95]. A prospective study by Shimoda [96] followed 125 patients with aneurysmal SAH with MRIs immediately after securing of the aneurysm, 3 days after SAH, 14
days after SAH, and 30 days after SAH. They reported

asymptomatic cerebral infarction rates of 23 %. This may be
due to the sensitivity of MRI for small ischemic events and
may actually represent a higher rate of cerebral infarction
than we know, as most studies use CT as the imaging modality of choice. Clinical exam is accurate for identifying
patients with symptomatic vasospasm and DINDs when
compared to CT findings; however, asymptomatic cerebral
infarctions are still missed, especially in comatose patients
where the exam is limited. Further imaging modalities such
as TCDs, CTA, or angiography may be more beneficial for
comatose patients. Digital subtraction angiography (DSA)
remains the gold standard for diagnosis of cerebral vasospasm and for which all other modalities are compared.

Transcranial Doppler (TCD)
Transcranial Doppler (TCD) uses ultrasonography to evaluate the major cerebral blood vessels and monitor trends in
flow and velocity to diagnose patients at risk for developing
and those in cerebral vasospasm. This technique is extremely


552

dependent upon multiple factors including consistency of the
individual performing the exam, experience of the individual
performing the exam, vascular anatomy, age, intracranial
pressure (ICP), hematocrit, mean arterial blood pressure
(MAP), and patient anatomical factors allowing for viewing
of the temporal window [97]. Transcranial dopplers have
been shown to have a high specificity and positive predictive
value (PPV) for diagnosing vasospasm in the middle cerebral arteries (MCA). In a meta-analysis by Lysakowski [98],
TCD findings were compared with angiographic findings to
report sensitivity and specificity of TCDs for diagnosing

vasospasm. Those who were assumed to have vasospasm on
TCDs of the MCAs were found to have vasospasm on angiography with a sensitivity of 67 % and specificity of 99 %
with a PPV of 97 % and negative predictive value (NPV) of
78 %. However, if vasospasm was not predicted on TCDs, it
did not exclude vasospasm diagnosed by angiography. They
concluded that TCD of the MCA was not likely to show
vasospasm if the angiography was negative (high specificity), and that TCDs may be used to identify patients with
vasospasm (high PPV). All other vessels studied did not have
sufficient data or evidence to support their use in diagnosing
vasospasm. Sloan [97] reported that when studying the
MCAs with TCD, certain criteria could reliably predict the
presence or absence of angiographic vasospasm. MCA flow
velocities of >200 cm/s, a rapid rise in flow velocities, and a
higher Lindegaard (vMCA/vICA) ratio (6 ± 0.3) were reliably predictive of angiographic vasospasm. An MCA velocity below 120 cm/s also reliably predicted the absence of
angiographic vasospasm. Sviri [99] similarly studied the
vertebra-basilar system with TCD and comparing them to
follow-up angiography. They found that the velocity ratio
between the basilar artery (BA) and the vertebral artery (VA)
correlated with angiographic vasospasm in the basilar artery.
They reported that BA/VA ratio >2 had a 73 % sensitivity
and 80 % specificity for basilar artery vasospasm. A ratio
higher than 2.5 with BA velocity greater than 85 cm/s was
associated with 86 % sensitivity and 97 % specificity for BA
narrowing of more than 25 %. A BA/VA ratio higher than 3.0
with BA velocities higher than 85 cm/s was associated with
92 % sensitivity and 97 % specificity for BA narrowing of
more than 50 %; however, the NPV and PPV were not
reported. The presence of vasospasm based on TCD or angiographic data does not predict DCI or DINDs.

Computed Tomographic Angiogram (CTA)

The use of CTA for the diagnosis of vasospasm is quick,
noninvasive, and easily available. CTA is also useful for the
quick diagnosis of postoperative bleeding, rehemorrhage,
stroke, hydrocephalus, or retraction edema when evaluating
for causes of neurologic decline. Almost all studies comparing CTA to DSA for diagnosis of vasospasm are fairly consistent. CTA seems to underestimate the diameter of large

M.M. Kimball et al.

cerebral arteries and overestimate the distal smaller cerebral
vessels. Surgical clips or coils can lead to artifact and make
it difficult to fully evaluate the vessels. CTA has a high accuracy, sensitivity, and specificity for diagnosing severe vasospasm or no vasospasm in larger proximal arteries but loses
accuracy in detecting it in distal, smaller vessels when compared to DSA [100, 101]. CTA tended to overestimate the
degree of vasospasm when there was a discrepancy. The use
of CTA as a screening tool may significantly limit the number of DSA done to diagnose vasospasm; however, CTA is
limited in that it lacks the ability to use intra-arterial methods
to treat vasospasm.

Vasospasm Prophylaxis and Management
Triple-H Therapy
Triple-H therapy, also known as hypertension, hypervolemia,
and hemodilution, has been used since the 1970s in the prophylactic management and treatment of vasospasm following SAH. The idea behind triple-H therapy is to expand the
intravascular volume with crystalloid and colloid to increase
leptomeningeal collateral perfusion to areas that have been
restricted by vasospasm, and improve inflow to counteract
vascular resistance, while at the same time diluting the blood
viscosity to improve flow rheology to brain tissue.
Prophylactic triple-H therapy is that which is done prior to
any evidence of vasospasm or clinical decline, whereas therapeutic triple-H therapy is instituted when vasospasm is suspected. The difficulty in studying the literature is that there is
no standardization for triple-H therapy for blood pressure
parameters or goal hemoglobin levels. Egge [102] randomized 16 patients to prophylactic triple-H therapy and 16

patients to euvolemic therapy. Triple-H therapy was associated with more complications, higher cost, and had no significant difference in vasospasm rates or improvements in
TCD velocities when compared to the euvolemic group.
Lennihan [103] randomized 82 patients to receive hypervolemia therapy or euvolemic therapy. Cardiac filling pressures
were noted to be higher with hypervolemic therapy, but without any evidence of increased cerebral blood flow and significant difference were seen on GOS at 2 weeks, 6 months,
or 1 year between the two groups. Complications have been
directly attributable to prophylactic triple-H therapy including pulmonary edema and worsening intracranial edema
with hemorrhagic transformation [104, 105]. Prophylactic
hemodilution has not shown to add any benefit to outcome or
vasospasm risk and has the negative effect of decreasing
oxygen carrying capacity and cerebral oxygenation. The
overall benefit of prophylactic triple-H therapy is not clear
and may pose significant physiologic risks including myocardial infarction, pulmonary edema, cerebral edema, renal
failure, and even potential rupture of additional intracranial


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Aneurysmal Subarachnoid Hemorrhage: Evidence-Based Medicine, Diagnosis, Treatment, and Complications

aneurysms. Prophylactic triple-H therapy is not recommended; however, hypotension should be avoided.
Therapeutic induced hypertension and volume expansion
have been shown in small studies to improve neurologic deficits if started after the onset of symptoms. Multiple pressors
have been studied and many MAP and SBP goals have been
suggested. Systolic blood pressures of 160–200 mmHg are
commonly quoted for goals, but patient-specific factors need
to be taken into account such as baseline cardiac and pulmonary disease. The limited data support that induced hypertension with pressors and volume expansion may improve
neurologic deficits but may be at the risk of pulmonary
edema, myocardial infarction, and hyponatremia. No randomized trials exist evaluating benefit and risk of induced
hypertension in patients that develop a neurologic deficit felt
to be secondary to cerebral vasospasm.

Calcium Channel Blockers
Calcium channel blockers act by inhibiting the flow of calcium into arteriolar smooth muscle, causing vascular dilation, and therefore are felt to reduce vasospasm in the
cerebral vasculature. Many calcium channel blockers exist;
however, the four that have been the most studied for vasospasm prevention are nimodipine, nicardipine, nitroprusside,
and verapamil. Nimodipine is the most well-studied drug for
vasospasm prophylaxis. It has been shown to have a significant reduction in the incidence of symptomatic vasospasm for
patients that received oral nimodipine compared to placebo
[106]. The largest randomized clinical trial for nimodipine
[107] showed significant reductions in the incidence of cerebral infarction and poor clinical outcome for patients treated
with oral nimodipine. Nicardipine has similar pharmacology
to nimodipine. It has been studied and used in many forms
including intravenous (IV), intra-arterial (IA), intrathecal
(IT), and as prolonged-release implants (NPRI). Two randomized controlled trials showed significantly reduced incidence of symptomatic vasospasm when nicardipine was used
compared to placebo [108, 109]. Nitroprusside is a medication that is pharmacologically broken down into nitrous oxide
which causes relaxation of vascular smooth muscle leading
to vasodilation. It is usually used intrathecally due to its short
half-life in the blood. One small prospective non-randomized
case-control trial showed improved TCD velocities, but large
studies are limited on this medication. Verapamil is another
calcium channel blocker which specifically blocks the L-type
calcium channel. It has been studied in the intra-arterial form
in case series with variable results. Among the calcium channel blockers, nimodipine was shown in more randomized controlled trials to significantly reduce symptomatic vasospasm
and improve outcomes. A recent meta-analysis on calcium
channel blockers showed an overall reduction in poor outcome compared to placebo, with the oral route of nimodipine
having the largest reduction in poor clinical outcome [110].

553

Magnesium Sulfate

Magnesium sulfate directly acts on and antagonizes voltagedependent calcium channels, which prevents vascular
smooth muscle contraction. It has also been shown to have a
neuroprotective benefit which is believed to be from blocking
N-methyl-D-aspartate (NMDA) receptors and inhibiting the
release of glutamate in tissues. Magnesium sulfate is commonly administered by the intravenous route after SAH.
Magnesium has been well studied for the prevention of vasospasm. Randomized controlled trials have shown a statistically significant decrease in symptomatic vasospasm when
compared to placebo [111], a trend toward reduced MCA
TCD velocities and improved clinical outcome [112], a nonsignificant reduction in DCI and poor clinical outcomes at 3
months [113], and a trend toward improved clinical outcomes at 3 months [114]. A meta-analysis [115] done in
2009 reported a statistically significant reduction in poor
outcomes including dependency and vegetative state. Known
complications of magnesium sulfate infusion include hypocalcemia and hypotension. The evidence shows a significant
improvement in outcome possibly from its neuroprotective
benefits and a reduction in symptomatic vasospasm in some
studies but in others only shows nonsignificant trends toward
improved outcome. The evidence is inconclusive at this time
and large randomized controlled trials are currently being
done for magnesium in SAH.
Statins
Statins, also known as hydroxymethylglutaryl coenzyme-A
reductase inhibitors (HMG-CoA reductase inhibitors) are
well-known cholesterol-lowering medications that have been
shown to decrease inflammation, inhibit thrombogenesis,
and induce nitric oxide synthase. Multiple randomized controlled trials (RCT) have been done showing promising
results. A meta-analysis of three RCT showed a statistically
significant reduction in vasospasm incidence and mortality
[116]. Tseng [117] first reported the results of statin use in
SAH in 2005. This RCT studied pravastatin versus placebo,
which showed a significant reduction in vasospasm incidence, DINDs, and mortality. A RCT by Lynch [118] produced similar results using simvastatin versus placebo where
the treatment group showed a significant reduction in vasospasm. Kramer [119] published the most recent metaanalysis of six randomized clinical trials showing a significant

reduction in DINDs and a trend toward decreased mortality
in those given a statin after aneurysmal SAH. No notable
side effects have been reported with statin use after SAH
except for the known small risks of elevated liver enzymes
and muscle breakdown with general statin use.
Endothelin Receptor Antagonists
Endothelin is a peptide that acts on vascular smooth muscle causing long-acting and severe vascular constriction.


554

Clazosentan and bosentan are two different endothelin receptor antagonists (ERA) that have been studied in humans.
One of the largest and most recent randomized controlled
studies [119] assigned 313 patients to receive dose-escalated
clazosentan and compared them to 96 placebo patients.
A significant reduction in moderate and severe vasospasm
was noted in the clazosentan group when given at the high
dose compared to placebo, and there was also a reduction
in the development of DIND and DCI. Endothelin receptor
antagonists are showing promise in the prevention of vasospasm, and further studies are currently being done.

Other Medical Treatments
Many other medical management options for the treatment
and prevention of vasospasm and DINDs have been studied.
Most of the following have been studied in smaller studies
with variable results. Fasudil is a rho-kinase inhibitor administered by the intravenous route that has been studied in
Japan. In one RCT [120], it was shown to have a significant
reduction in angiographic and symptomatic vasospasm, lowdensity areas on CT, and improved 1-month Glasgow outcome scores (GOS) when compared to placebo. In a second
RCT [121], it was shown to have a nonsignificant reduction
in symptomatic vasospasm when compared to nimodipine.

The use of thrombolytics such as urokinase and tissue
plasminogen activator (tPA) have been studied for intrathecal use, with the theory that they will break down subarachnoid blood products and decrease the irritation of the blood
vessels and prevent vasospasm. Only 2 RCT have been done.
One large randomized controlled trial [122] using urokinase
showed a significant reduction in symptomatic vasospasm
and improved GOS at 6 months compared to placebo when
used intrathecally after aneurysm coiling. The second study
[123] used intrathecal tPA after aneurysm clipping and was
noted to have a trend toward reduced vasospasm severity but
was not significant. The data on thrombolytic use are variable and cannot be recommended for use based on current
literature.
Papaverine is a well-known cerebral and coronary vasodilator. Its exerts its mechanism of action by inhibiting cyclic
adenosine monophosphate (cAMP) and cyclic guanosine 3,5
(cGMP) phosphodiesterase activity. Papaverine has been
delivered by many mechanisms including intracisternal use,
as a pellet form left at the time of surgery, and intra-arterially
by endovascular means. Prophylactic studies using the pellet
delivery system and intracisternal use are small; however,
they did show some improvement in neurologic outcome and
symptomatic vasospasm. No randomized controlled trials
have been done to study papaverine in SAH, but nonrandomized case-control studies have been reported. Intraarterial (IA) papaverine given, not prophylactically, but
instead for the treatment of vasospasm has been reported to
have both improvement in angiographic vasospasm and

M.M. Kimball et al.

clinical symptoms. Kassel [124] was the first to use IA
papaverine as a single agent for vasospasm treatment, with
two-thirds of patients showing angiographic improvement
and one-third showing clinical improvement.

Many other medical therapies have been studied for the
prevention and treatment of vasospasm; however, they are
small studies. Some of these include antifibrinolytics, thromboxane synthetase inhibitors, low-molecular-weight heparin,
and intravenous erythropoietin.

Endovascular Interventions
Medical management of vasospasm consists generally of a
combination of medications to prevent vasospasm, as indicated previously. When vasospasm occurs, however, medical
options typically only include triple-H therapy, which is
associated with many medical complications including heart
failure, pulmonary edema, and myocardial infarction.
Endovascular interventions include intra-arterial administration of vasodilators (Fig. 24.2a) or transluminal balloon
angioplasty (TBA) (Fig. 24.2b).
Transluminal balloon angioplasty is the act of dilating the
intracranial arteries with a small balloon. This technique has
been used both prophylactically prior to vasospasm and as a
therapeutic modality after vasospasm develops. Angioplasty
can be used alone or in combination with IA vasodilators
such as papaverine and verapamil. Prophylactic TBA was
studied in an RCT [125] where 85 patients with SAH underwent TBA of bilateral A1, M1, P1, basilar, and intradural
portion of the dominant vertebral artery within 96 h of hemorrhage. Patients who underwent TBA had a trend toward a
reduction in DINDs and also had a significant reduction
compared to placebo in those requiring therapeutic angioplasty. The risks of TBA include vessel perforation, hemorrhage, and death and are higher if TBA is performed distally
in the vessels. During this study, prophylactic angioplasty of
the A1 and P1 segments was discontinued due to complications. Prophylactic balloon angioplasty, despite showing a
decrease in the need for therapeutic angioplasty, is not recommended due to the risk of vessel perforation and no significant improvement in overall outcome.
Although TBA is not recommended for prophylaxis of
vasospasm, it is successful in the treatment of vasospasm
when it does develop. Vessels that are treated successfully
have been shown to reduce the incidence of DCI [126, 127].

The timing of endovascular intervention after development
of cerebral vasospasm has not been well defined. Two studies have reported the timing of endovascular intervention,
analyzing early versus delayed intervention after the onset of
cerebral vasospasm. Rosenwasser [128] retrospectively
reviewed 84 patients that underwent balloon angioplasty
with or without IA papaverine. Fifty-five patients were
treated within 2 h of neurologic decline, and 33 patients were
treated greater than 2 h after neurologic decline. Patients that


24

Aneurysmal Subarachnoid Hemorrhage: Evidence-Based Medicine, Diagnosis, Treatment, and Complications

555

a

b

Fig. 24.2 (a, b) Cerebral vasospasm. (a) Intra-arterial verapamil treatment. Left panel, focal vasospasm of M2 branch of the left middle cerebral artery (arrowhead). Middle panel, microcatheter injection of
verapamil into the affected branch vessel. Right panel, immediate
improvement in vessel diameter after intra-arterial verapamil treatment

(arrowhead). (b) Transluminal balloon angioplasty. Left panel, vasospasm of the right middle cerebral artery after clipping of a ruptured
right middle cerebral bifurcation aneurysm. Right panel, immediate
improvement in vessel diameter after transluminal balloon angioplasty
of the right middle cerebral artery

were treated within 2 h had a significantly better neurologic

improvement than those that had delayed treatment. Bejjani
[129] reported similar findings when they retrospectively
studied 21 patients treated within 24 h of neurologic decline
and 10 patients treated greater than 24 h after neurologic
decline. They reported a more significant improvement in
those that underwent early treatment compared to those that
had delayed treatment.
The use of intra-arterial agents during endovascular treatment of cerebral vasospasm offers direct delivery of vasodilators to the vessels in vasospasm. Three medications have
been well studied for intra-arterial delivery for vasospasm,

papaverine, nicardipine, and verapamil. There have been
many case series using IA papaverine showing successful
treatment of cerebral vasospasm with both good clinical and
angiographic results. Nicardipine in the IA form has been
evaluated in retrospective studies to improve angiographic
vasospasm and transiently improve neurologic deficits [130].
Verapamil has been shown in retrospective studies to show
improvements in arterial diameter without significant side
effects [131, 132]. Any agent may be chosen for IA therapy,
and dose is limited by systemic hemodynamic response.
Further studies need to be done to determine if any agent is
more efficacious.


556

Medical Complications of Subarachnoid
Hemorrhage
Medical complications are frequent after SAH and increase
the morbidity and mortality; however, they can be managed

if recognized early. The Aneurysm Cooperative Study [133]
reported the frequency of having at least one life-threatening
medical condition after SAH to be 40 %, with a proportion of
the deaths from a medical complication to be 23 %. This rate
is similar to that quoted to the causes of death from the initial
hemorrhage which was 19 %, rehemorrhage which was
22 %, and vasospasm which was 23 %. Pulmonary edema
was reported in 23 % of patients, with a 6 % rate of severe
pulmonary edema. Renal dysfunction was noted to be 7 % in
the whole group, with 15 % of that group that developed
severe, life-threatening renal dysfunction. Pulmonary complications were noted to be the most common non-neurologic
cause of death. Thrombocytopenia, hepatic dysfunction, and
hyponatremia are metabolic disturbances that are also associated with SAH and need to be routinely monitored.

Cardiac and Pulmonary Complications
Cardiac and pulmonary complications have been well documented after aneurysmal SAH. The relationship between
SAH and myocardial injury or dysfunction has been hypothesized to be secondary hypothalamic dysfunction or hyperdynamic response to catecholamine release after SAH.
Although there has been no specific cause identified, there is
clearly an association between the two. It has been shown in
clinical studies that there are elevated catecholamine levels
early after SAH [134, 135] and that cardiac lesions after
SAH when studied pathologically appear very similar to
those found in catecholamine-induced myocardial necrosis
[136]. It is not felt that cardiac dysfunction is from acute
coronary spasm or disease; however, these must be ruled out
in patients with cardiovascular risk factors.
Recognizing cardiac and pulmonary complications early
better allow the team to maximize medication choices for
volume status and induced hypertension if needed. Two of
the most commonly studied variables for understanding cardiac dysfunction after SAH are troponin levels and wall

motion abnormalities (WMA), also known as regional wall
motion abnormalities (RWMA) diagnosed by echocardiography. A large meta-analysis [137] including 2,690 patients
from 25 studies, 16/25 studies being prospective, evaluated
cardiac complications after SAH and their effect on outcome. Elevation of troponin I was noted in 34 % of patients
which was associated with cardiac dysfunction. Poor outcome was associated with elevated troponin levels (RR 2.3)
and ST-segment depression (RR 2.4). Factors associated
with mortality included wall motion abnormalities (WMA)

M.M. Kimball et al.

(RR 1.9), elevated troponin (RR 2.0) and brain natriuretic
peptide (BNP) levels (RR 11.1), tachycardia (RR 3.9), Q
waves (RR 2.9), ST-segment depression (RR 2.1), T-wave
abnormalities (RR 1.8), and bradycardia (RR 0.6).
Occurrence of DCI was associated with WMAs (RR 2.1);
elevated troponin (RR 3.2), CK-MB (RR 2.9), and BNP levels (RR 4.5); and ST-segment depression (RR 2.4). There is
some variation among these studies of what is considered
elevated troponin, which had a range of 0.1–1 ng/ml.
Diastolic dysfunction has been reported to occur in 71–89 %
[138, 139] of patients after SAH and has been associated
with development of pulmonary edema.
Electrocardiogram (ECG) changes are common after
SAH and include deep T-wave inversion and QT prolongation. A report by the Cooperative Aneurysm Study [133]
reported a frequency of life-threatening cardiac arrhythmias
of 5 %, with other cardiac dysrhythmias occurring in about
30 % of patients. Ventricular arrhythmias were more common if troponin I was elevated [140]. No current randomized
controlled trials exist evaluating the use of invasive cardiovascular monitoring and its effect on morbidity and mortality
after SAH. At this time, the need for invasive cardiovascular
monitoring should be evaluated on a patient-by-patient basis.
The prophylactic placement of invasive monitoring, excluding arterial lines, is not indicated by the data; however, it may

be helpful in preventing cardiopulmonary complications if
hyperdynamic or hypertensive therapy is being used.
Frequent monitoring of electrolytes and correction of metabolic disturbances such as magnesium and potassium can
help prevent arrhythmias.
Wall motion abnormalities (WMA) after SAH are well
reported and typically involve left ventricular dysfunction.
Kothavale and coworkers [141] prospectively studied 300
patients with aneurysmal SAH with serial echocardiography
with a primary outcome of measuring the presence of
RWMA. Eight hundred and seventeen echocardiograms
were analyzed and RWMA were found in 18 % of patients.
Patients with higher admission Hunt-Hess grades had higher
rates of RWMA. Patients with Hunt-Hess grades 3–5 had an
incidence of 35 %. There was also an association between
elevated troponin I and RWMA, where 65 % of patients with
troponin I levels greater than 1mcg/L had RWMA. They also
reported prior use of cocaine or amphetamine were independent predictors of RWMA. A study by Sugimoto and coworkers [142] studied the prognostic significance of RWMA on
outcome. They prospectively enrolled 47 patients after aneurysmal SAH and performed early echocardiography and
ECG, within 3 days of SAH. They recorded the incidences of
pathologic ECG changes, global hypokinesia defined as a
left ventricular ejection fraction (LVEF) <50 %, and RWMA.
The incidence of pathologic ECG changes was 62 %, LV
ejection fraction <50 % was 11 %, and RWMA was 28 %.
Rate-corrected QT interval, LV ejection fraction <50 %, and


24

Aneurysmal Subarachnoid Hemorrhage: Evidence-Based Medicine, Diagnosis, Treatment, and Complications

RWMA were all significant predictors of death. A specific
form of RWMA more commonly being recognized in SAH
is what is termed takotsubo cardiomyopathy. This form of
cardiomyopathy is defined by left ventricular dysfunction
consisting of akinesia of predominantly the apex and midventricle with relative sparing of the basal segment, which
gives it a typical appearance on echocardiography.
Cardiomyopathy seen in SAH, commonly called neurogenic
stress cardiomyopathy (NSC), is defined by hypokinesia of
the basal and midventricular portions with relative sparing of
the apex. Most cardiomyopathies induced after SAH are
believed to be secondary to catecholamine release and not
coronary in nature and are felt to be mostly reversible [143].
The original descriptions and studies of takotsubo cardiomyopathy excluded patients with traumatic brain injury and
SAH and were not well understood in patients with neurologic diseases. Lee and colleagues [144] reported the largest
study of takotsubo cardiomyopathy in SAH patients. They
retrospectively reviewed all patients with SAH admitted to
the Mayo Clinic Neurological Intensive Care Unit between
1990 and 2005 and found 24 patients that had SAH-induced
reversible cardiac dysfunction, and of those, eight met echocardiographic criteria for takotsubo cardiomyopathy. All
eight patients were women with a mean age of 55.5. Seven
patients presented with Hunt-Hess grade III or IV. Four
patients underwent coil embolization and four underwent
surgical clipping. The mean initial ejection fraction (EF) was
38 %, and the mean EF at recovery was 55 %. Six of the eight
patients developed cerebral vasospasm, but only 3 developed
cerebral infarction. Takotsubo cardiomyopathy is a rare form
of cardiomyopathy after SAH and is more common in postmenopausal women; is associated with pulmonary edema,
prolonged intubation, and vasospasm; but is a reversible
form of cardiomyopathy similar to the other neurogenic
stress cardiomyopathies.

Pulmonary complications are common after SAH and are
the leading non-neurologic cause of morbidity and mortality
after aneurysmal SAH. In retrospective trials it is difficult to
assess the cause of the pulmonary edema, but it has been
documented in the literature to be around 27 %. In one study
[145] this was defined by a pulmonary arterial O2 (PaO2) to
fraction of inspired O2 (FiO2) ratio (PaO2/FiO2) of <300.
A second study [146] used evidence of bilateral pulmonary
infiltrates on chest x-ray and found similar incidence of pulmonary edema. Hypervolemia therapy has not shown to have
a significant benefit on neurologic outcome and is associated
with medical complications including pulmonary edema.
Kim and colleagues [147] retrospectively reviewed prospectively collected data on 453 patients after SAH. They were
divided into two groups: group 1 were those that were treated
with hypervolemic and hypertensive therapy, and group 2
were those that were treated with euvolemic therapy. The
rate of pulmonary edema decreased from 14 to 6 % between

557

groups 1 and 2, respectively, and mortality had also decreased
from 34 to 29 % between groups 1 and 2, respectively.
Patients with pulmonary edema and or cardiac dysfunction
may benefit from invasive cardiovascular monitoring to aim
for a euvolemic goal to decrease left ventricular dysfunction
from volume loading and appropriate balance volume status
to improve pulmonary edema.

Anemia and Transfusion
Blood transfusion has always been a controversial topic
among physicians treating medical and surgical patients. The

risk of blood transfusion includes minor and severe transfusion reactions, and the risk of HIV and hepatitis transmission. Recent data have suggested that patients can tolerate
lower hemoglobin levels than we previously thought, and
that there may be adverse outcomes associated with blood
transfusions. Marik [148] reviewed forty-five studies that
reported the independent effect of red blood cell transfusion
(RBCT) on patient outcomes. In forty-two of the 45 studies,
the risks of RBCT outweighed the benefits, the risk was neutral in two studies, and the benefits outweighed the risks in a
subgroup of one study which included elderly patients with
acute myocardial infarction and a hematocrit (HCT) less
than 30 %. Seventeen of the 18 studies that studied death as
a primary outcome showed that BRCT was an independent
predictor of death. All twenty-two studies that evaluated the
association of RBCT and infection showed that RBCT was
an independent predictor of infection. There was also significant association between RBCT and development of multisystem organ failure and acute respiratory distress syndrome
(ARDS).
There has also been great debate on what levels of hemoglobin are thresholds for transfusion. The Transfusion
Requirements in Critical Care Trial (TRICC) [149] studied
two thresholds for transfusion termed “liberal,” defined as
hemoglobin (Hgb) of 10 g/dl versus “restricted,” defined as
Hgb of 7 g/dl in 883 ICU patients. The overall 30-day mortality was similar between the two groups, except for those
who were younger and less ill where mortality was less in the
restrictive RBCT group. Few studies have evaluated RBCT
and its effect on patients with brain injury. The best study we
have for brain injury patients is a subgroup of the TRICC
trial who sustained severe closed traumatic brain injury
(TBI) [150]. Twenty-nine patients were randomized to the
restrictive (Hgb 7 g/dl) group, and 38 were randomized to the
liberal (Hgb 10 g/dl) group. There were no significant differences between the two groups in overall mortality, multisystem organ failure, length of ICU, or length of hospital stay. It
is difficult to extrapolate these data to SAH patients who
commonly have cardiac dysfunction and may benefit from a

liberal Hgb level. The goal in SAH is to maintain normal


558

circulating volume with adequate tissue oxygen delivery. It
is a complex relationship between the understanding of adequate tissue oxygenation, volume status, current cardiac and
pulmonary dysfunction, and primary medical conditions.
Animal studies [151] have shown that a Hgb <10 g/dl is associated with brain hypoxia, and correction with RBCT may
improve brain tissue oxygenation, especially in a brain after
SAH where normal compensatory cerebrovascular response
may be damaged. Preventing hypoxia should be a goal of
SAH patient management, as there are limited studies of how
RBCT affects patients after SAH. Observational studies
show that RBCT can cause medical complications as noted
earlier, and there are no consistent data that RBCT improves
brain tissue oxygenation. As in many of the RBCT trials, it is
often difficult to assess whether RBCT is in fact associated
directly with mortality or that those requiring transfusions
with persistently low Hgb (7 g/dl) are more critically ill and
at baseline have a higher mortality and that transfusion is
needed because of that. Anemia is a risk factor for poor outcome after SAH, but it is not clear whether this is an independent risk factor or a measure of the severity of disease. At
this time there are no randomized controlled trials or large
studies to suggest a threshold hemoglobin level for which
SAH patients should be transfused, and each patient should
be treated on an individual basis.

Hyponatremia
Hyponatremia is the most common electrolyte abnormality
in patients after SAH. It is commonly defined as a serum

sodium <135 mmol/l and has been reported to occur in about
30–50 % of aneurysmal SAH patients [152, 153].
Hyponatremia in SAH are often attributed to one of two different mechanisms called cerebral salt wasting (CSW) and
syndrome of inappropriate antidiuretic hormone secretion
(SIADH). Each of these processes is pathophysiologically
different but appears similarly in lab values. Both are associated with low serum sodium and abnormally elevated urine
sodium. The mechanism behind CSW is felt to be caused by
sympathetic discharge after SAH which stimulates the
release of natriuretic peptides causing sodium loss in the
urine. This sodium loss causes an osmotic gradient across
the tubules, which pulls water with it into the urine, causing
an excess of urine output. This excessive urine output causes
overall systemic hypovolemic hyponatremia. SIADH is
caused by an inappropriate excretion of antidiuretic hormone, causing water reabsorption in the kidney leading to
euvolemic or slightly hypervolemic hyponatremia. The ability to measure intravascular volume with central venous lines
and strict ins and outs is imperative in diagnosis but also
treatment.

M.M. Kimball et al.

Recognition and management of hyponatremia is important because hyponatremia can cause worsening cerebral
edema by causing a gradient for water to move into the cerebral space, increasing intracranial pressure and exacerbating
neurologic deficits. Hyponatremia by itself is associated with
seizures especially at levels <125 mmol/l and in a patient
with intracranial pathology places them at increased risk and
lowering the threshold for seizures. Hyponatremia has not
been associated with worse neurologic outcome.
Treatment strategies aim at raising the sodium slowly,
due to the risk of central pontine myelinolysis and aim
for normonatremia (135–145 mmol/l). Common treatment options include mineral corticoids and hypertonic

saline. Fludrocortisone is a mineralocorticoid often used
in the treatment of hyponatremia associated with SAH.
Mineralocorticoids act on the renal tubules to form channels
that reabsorb sodium from the kidneys, while causing excretion of potassium. Fludrocortisone has the advantage over
hydrocortisone of not significantly altering serum glucose
levels. There does not appear to be any significant increase
in pulmonary edema or congestive heart failure with fludrocortisone use [154]. Hypertonic saline, commonly in the 3 %
concentration, is another treatment option for hyponatremia.
It can be given as boluses or run as a continuous infusion.
Continuous infusions are more commonly given unless seizures occur or acute cerebral edema is present, in which
case boluses may be more effective, followed by a continuous infusion to maintain normonatremia. Even though the
common treatment for isolated SIADH is volume restriction,
in the setting of SAH and vasospasm, this can be dangerous and place the patient at risk for DCI and vasospasm and
is not recommended [155]. Sodium should be corrected by
the hypertonic saline route, and fludrocortisone may also be
used. Only observational studies exist for the use of hypertonic saline and fludrocortisone for hyponatremia in SAH,
which both show safety of their use but no definitive dose or
duration of treatment can be suggested based on the literature at this time.
Conclusions

Aneurysmal subarachnoid hemorrhage is a multifactorial
disease process that requires a treatment team of neurosurgeons and neurointensivists to maximize each patient’s
outcome. This chapter encompasses the best literature
available at the time of publication to manage the intricacies of aneurysmal subarachnoid hemorrhage. There is a
vast amount of literature available; however, many uncertainties exist in the literature, and current studies are being
done to better optimize our treatment of these patients. At
the University of Florida, we have developed treatment
practices for the management of aneurysmal SAH patients
as outlined in Table 24.5.

24

Aneurysmal Subarachnoid Hemorrhage: Evidence-Based Medicine, Diagnosis, Treatment, and Complications

Table 24.5 Management practice for aneurysmal SAH patients at the
University of Florida
Treatment protocol
Admission to neurosurgical ICU
CT angiogram of head and neck with perfusion
Radial arterial line
Strict systolic BP goals <140 mmHg (until aneurysm secured)
Loaded with fosphenytoin and continued for 3 days unless seizures
occur or intraparenchymal hemorrhage
Ventriculostomy placement if hydrocephalus on CT scan or GCS 13
or less
Aminocaproic acid IV infusion for 12–24 h until aneurysm secureda
Nimodipine 60 mg PO every 4 h for 14–21 days
Zocor 40 mg PO dailya
Magnesium sulfate infusion for 14 days (renally dosed)a
Daily transcranial dopplers
Hunt-Hess grades 1–3 undergo coiling or clipping within 24 h
Hunt-Hess grades 4–5 undergo ventriculostomy, if improvement
undergoes treatment
Once aneurysm secured, systolic blood pressure range
100–180 mmHg
No prophylactic HHH therapy
If neurologic decline, CT angiogram with perfusion obtained
If vasospasm present on CT angiogram pt taken to angio suite
a

Optional

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Intracerebral Hemorrhage:
Evidence-Based Medicine, Diagnosis,
Treatment, and Complications

25

Chad W. Washington, Ahmed N. Hassan,
and Gregory J. Zipfel

Contents
Introduction ................................................................................... 565
Epidemiology ................................................................................. 566
Incidence ......................................................................................... 566
Risk Factors ...................................................................................

Age ..................................................................................................
Race/Ethnicity .................................................................................
Hypertension ...................................................................................
Cerebral Amyloid Angiopathy ........................................................
Antithrombotic Medications ...........................................................

566
566
566
567
567
567

Clinical Presentation ..................................................................... 567
Morbidity and Mortality .............................................................. 568
Imaging Diagnostics ......................................................................
Computed Tomography (CT) ..........................................................
Computed Tomographic Angiography (CTA) ................................
Magnetic Resonance Imaging (MRI)..............................................
Digital Subtraction Angiography (DSA) ........................................
Recommendations ...........................................................................

568
568
569
570
570
571

Medical Management ...................................................................

Prevention of Hematoma Expansion and Rebleeding.....................
Maintaining Cerebral Perfusion: Blood Pressure Management......
Treatment of Cerebral Edema .........................................................
Seizures ..........................................................................................
General Care ...................................................................................

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C.W. Washington, MS, MPHS, MD
Department of Neurological Surgery,
Washington University in St. Louis,
660 S Euclid, 8057, St. Louis, MO 63110, USA
e-mail:
A.N. Hassan, MD
Department of Neurology/Neurocritical Care,
Washington University School of Medicine,
660 S. Euclid Ave, 8111, St. Louis, MI 63110, USA
e-mail:
G.J. Zipfel, MD (*)
Department of Neurosurgery,
Barnes-Jewish Hospital, 660 S. Euclid,
8057, St. Louis, MO 63110, USA
e-mail:
A.J. Layon et al. (eds.), Textbook of Neurointensive Care,
DOI 10.1007/978-1-4471-5226-2_25, © Springer-Verlag London 2013

Surgical Management ...................................................................
Supratentorial Hemorrhage .............................................................
Cerebellar Hemorrhage ...................................................................
Intraventricular Hemorrhage and Hydrocephalus ...........................
Recommendations ...........................................................................

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References ...................................................................................... 574

Abstract

The treatment of primary intracranial hemorrhage (ICH) is
one of the most difficult problems facing neurologists, neurosurgeons, and neurointensivists today, and with an incidence of 10–30 cases per 100,000, it represents a major
medical problem. In spite of marked advances in medical
technology, the outcomes for patients suffering from a spontaneous ICH remain bleak with mortality rates reaching
62 % within the first year of onset. The difficulty in treating
these patients has resulted in substantial research efforts into
establishing an appropriate management scheme for ICH.
The purpose of this chapter is to consolidate this information and provide the clinician with evidence-based, upto-date treatment guidelines for primary ICH. The reader
will be led through a discussion of the most current epidemiologic data, use of diagnostic imaging, medical management, and role of surgical intervention. While a
significant number of questions exist regarding treatment
strategies, following each section is a synopsis of the current literature with treatment recommendations.
Keywords

Primary intracranial hemorrhage • Hemorrhagic stroke •
Hypertension • Cerebral amyloid angiopathy • Cerebellar
hemorrhage • STICH

Introduction
Intracerebral hemorrhage (ICH) is the end result of a number
of pathophysiologic processes where blood is extravasated
into the brain parenchyma [1]. These processes are divided
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Table 25.1 Causes of spontaneous intracranial hemorrhage

Secondary

Hypertension
Cerebral amyloid angiopathy
Aneurysm
Vascular malformations
Vasculitis
Venous thrombosis
Neoplasm
Antithrombotics (i.e., warfarin, antiplatelet medication)
Coagulopathy
Drugs

into either primary or secondary ICH (Table 25.1). Primary

ICH refers to hemorrhage resulting from hypertension or
cerebral amyloid angiopathy (CAA) [1]. The focus here will
be the diagnosis and management of primary ICH. While
many of the principles presented can be applied to the treatment of secondary ICH, we direct the reader to the chapters
regarding aneurysmal subarachnoid hemorrhage (Chap. 24),
vascular malformations (Chap. 26), and CNS neoplasia
(Chap. 34) for details specific to these pathologies.
The treatment of ICH is one of the most difficult problems
facing neurologists, neurosurgeons, and neurointensivists
today. In spite of marked advances in medical technology, the
outcomes for patients suffering from a spontaneous ICH remain
bleak with mortality rates reaching 62 % within the first year of
onset [2]. The difficulty in treating these patients has resulted in
substantial research efforts into establishing an appropriate
management scheme for ICH. The purpose of this chapter is to
consolidate this information and provide the clinician with
evidence-based, up-to-date treatment guidelines for ICH.

Incidence of ICH as a function of age
250
Incidence per 100,000 person-years

Primary

200

150

100

50

0
≤44

45–54

55–64

65–74

75–84

≥85

Years

Fig. 25.1 Increasing incidence of ICH is highly correlated with
increasing age (Graph extrapolated from data by van Asch et al. [10])

Risk Factors
While the overall incidence of ICH has remained stable over
years, many studies show that a number of factors greatly
increase an individual’s chance of suffering an ICH [2]. Nonmodifiable risk factors include age, ethnicity, genetic factors,
and cerebral amyloid angiopathy; major modifiable risk factors
include hypertension and excessive alcohol consumption [11].

Age

Epidemiology

Worldwide, stroke is a major medical problem affecting over
15 million people each year [3] and accounting for 5.5 million deaths annually [1]. In the United States, it is the third
leading cause of death [4], and fiscal costs related to stroke
are thought to be in excess of $50 billion annually [1].

Incidence
Nontraumatic ICH makes up 10–15 % of reported strokes, with
primary ICH making up 78–88 % of these cases [2, 3, 5]. The
incidence of ICH varies greatly with regard to the population
being studied. There are a number of factors attributable to an
increase incidence in ICH (i.e., age, race, genetic predisposition, and hypertension), but in general rates are considered to
be in the range of 10–30 cases per 100,000 [6–9]. Interestingly,
in spite of significant efforts from the medical community to
address known risk factors for ICH, the incidence has not
appreciably decreased over the past 30 years [10].

Perhaps the single most important risk factor related to an
increase rate of ICH is advancing age [6, 9, 10]. Sacco and
colleagues found the incidence ranged from 1.8 per 100,000
in 0-to-44-year-olds compared to 308.8 per 100,000 in
patients over 85 years of age [9]. Similar results were noted
by van Asch and colleagues in their meta-analysis demonstrating an exponential progression in ICH incidence related
to age (Fig. 25.1) [10]. They found for patients 0–44 years of
age, the incidence was 1.9 compared to 196.0 per 100,000 in
patients over 85 years of age. Ariesen and colleagues calculated a relative risk with each 10-year increase in age of 1.97
(95 % CI, 1.79–2.16) [11].

Race/Ethnicity
There is a disparate representation of stroke in AfricanAmericans, who are affected at a rate of almost 2–1 compared to Caucasians [7, 8, 12, 13]. The reported incidence for
this high-risk population varies from 37 to 50 per 100,000

[7, 8, 12–14]. Much of this burden is carried by middle-aged