Curr Treat Options Neurol (2014) 16:278

DOI 10.1007/s11940-013-0278-x

CRITICAL CARE NEUROLOGY (KN SHETH, SECTION EDITOR)

Cerebral Vasospasm
After Aneurysmal
Subarachnoid Hemorrhage
and Traumatic Brain Injury
Saef Izzy, MD1
Susanne Muehlschlegel, MD, MPH1,2,3*
Address
*,1Department of Neurology (Neurocritical Care), University of Massachusetts
Medical School, 55 Lake Ave North, S-5, Worcester, MA 01655, USA
Email: susanne.muehlschlegel@umassmemorial.org
2
Department of Surgery, University of Massachusetts Medical School, 55 Lake
Ave North, S-5, Worcester, MA 01655, USA
3
Department of Anesthesiology/Critical Care, University of Massachusetts
Medical School, 55 Lake Ave North, S-5, Worcester, MA 01655, USA
Published online: 18 December 2013
* Springer Science+Business Media New York 2013

This article is part of the Topical Collection on Critical Care Neurology

Keywords Cerebral vasospasm I Angiographic vasospasm I Delayed cerebral ischemia I Traumatic brain injury I
Subarachnoid hemorrhage I Traumatic subarachnoid hemorrhage I Blast injury I Treatment I Aneurysmal
subarachnoid hemorrhage

Opinion statement
Cerebral vasospasm (cVSP) consists of the vasoconstriction of large and small intracranial vessels which can lead to cerebral hypoperfusion, and in extreme cases, delayed
ischemic deficits with stroke. While most commonly observed after aneurysmal subarachnoid hemorrhage (aSAH), cVSP can also occur after traumatic brain injury (TBI)
as we have described in detail in this review. For the past decades, the research attention has focused on cVSP because of its association with delayed cerebral ischemia,
which is the largest contributor of morbidity and mortality after aSAH. New discoveries
in the cVSP pathophysiology involving multifactorial complex cascades and pathways
pose new targets for therapeutic interventions in the prevention and treatment of
cVSP. The goal of this review is to demonstrate the commonalities and differences
in epidemiology and pathophysiology of both aSAH and TBI-associated cVSP, and highlight the more recently discovered pathways of cVSP. Finally, the latest cVSP surveillance methods and treatment options are illustrated.

Introduction
Cerebral vasospasm (cVSP) consists of the vasoconstriction of large and small intracranial vessels. It can lead to cerebral hypoperfusion, culminating in delayed ischemic

deficits with stroke. CVSP has most commonly been associated with aneurysmal subarachnoid hemorrhage
(aSAH), but can also occur in traumatic brain injury (TBI).

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Epidemiology of cVSP
For decades, the attention has focused on cVSP because of its association
with delayed cerebral ischemia (DCI), which is the largest contributor of
morbidity and mortality after aSAH [1, 2, 3]. Fifteen percent of intracranial
hemorrhages and 5 % of all strokes are due to aSAH from acute rupture of an
intracranial aneurysm, affecting 145/100,000 persons annually [1]. Following aSAH, 3070 % of patients will develop cVSP between day 4 and day
14 after aneurysm rupture. Approximately half of these patients will develop
DCI [1]. Compared to aSAH-related cVSP, data on TBI-associated cVSP is
sparse. The mechanistic etiologies of TBI-associated cVSP can be divided into
cVSP following traumatic SAH (tSAH) [4] and blast-related cVSP after nearby
high-explosive detonation.
TSAH has been reported to occur in 39 %65 % of all TBI cases [57],
with 10 %30 % having TBI-associated radiographic cVSP in the presence
of SAH on head computed tomography (hCT) [79]. Its presence has been
independently associated with poor functional outcome [6, 10, 11] albeit
SAH may just be a marker of more severe TBI and not causing cVSP. To date,
the largest study in tSAH (n=299) describing transcranial Doppler (TCD)
defined cVSP reported the incidence of TBI-related cVSP to be lower than
after aSAH [7]. It is not clear, however, whether this is due to a truly lower
incidence, or whether it is less commonly detected because it is not
suspected, and therefore, not routinely monitored.
Blast-related cVSP is often associated with the presence of SAH, but SAH is
not required for the development of cVSP [10, 12, 13], suggesting a different
underlying mechanism. Both in vivo and in vitro studies have suggested that
mechanical alteration of the cerebral blood vessels through direct impact or
stretch from the blast may trigger the development of cVPS [10, 14].
In contrast to aSAH-related cVSP, where the onset of cVSP is between 3
5 days after aSAH, lasting up to 1421 days [1], the onset of tSAH-related
cVSP has been reported as early as within 12 days after injury [5, 8], with a
peak at 57 days [10, 13]. The duration of tSAH-associated cVSP is generally
shorter than that of aSAH with complete resolution usually in less than
14 days [10, 13]. Blast-related cVSP, however, has been reported to have an
early onset within two days, with average cVSP duration of 14 days, lasting
up to 30 days [13].

Risk factors
ASAH-associated symptomatic cVSP and DCI share the same risk factors:
admission hypertension, poor clinical grade, thick cisternal clot and intraventricular hemorrhage (modified Fisher score 4) [1517]. In contrast, angiographic cVSP has been associated with younger age, tobacco use, poor
clinical grade, and intracerebral hemorrhage [15, 18]. TBI-related cVSP has
been associated with severe SAH on initial hCT and low Glasgow Coma
Scale (GCS) on admission; however, this relationship is less concrete
compared to aSAH [7, 9, 13].

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Clinically relevant definitions of cVSP and DCI

Multiple definitions of cVSP exist, making the standardization of treatments and research end points difficult. Recently, investigators from the
SAH Outcomes Project (Columbia University, New York, NY) reported
the clinically most important definitions of cVSP [15], which are summarized in Table 1.
DCI is clinically important as it has been independently associated with
mortality and poor 3-month outcome [15, 19]. DCI commonly develops
during the second week after SAH, peaking around day 9 [2]. Clinical
worsening, a key determinant of DCI, can be acute focal weakness or loss of
consciousness, but may be as subtle as worsening headaches [20], and
always has to be differentiated from rebleeding or other causes of deterioration such as seizures or sepsis-associated encephalopathy [1]. Therefore,
the diagnosis of DCI is limited in comatose and poorly responsive highgrade aSAH patients.
Extensive research has been conducted on the relationship between
angiographic cVSP and DCI and whether angiographic evidence of
cVSP is required for a diagnosis of DCI. In one study, only 84 % of a
DCI cohort had radiographic cVSP [15]. Furthermore, only 2435 % of
SAH patients imaged with hCT, and only 81 % imaged with magnetic
resonance imaging (MRI) displayed an area of cerebral infarction correlating with the vessel territory of the vessel in angiographic cVSP [21,
22]. This raises the possibility of other underlying mechanisms, as described below.
In TBI, the ability to detect clinically significant deficits is challenging due
to the commonly decreased level of consciousness in the patients, and heterogeneity of the disease mechanisms.

Table 1. Definitions of cVSP and DCI*

Type of cVSP

Definition

Symptomatic cVSP

Clinical worsening in the setting of new focal neurological signs, deterioration in level of
consciousness, or both, in the absence of other possible causes (seizures, hydrocephalus, and
edema); does not necessarily imply documented angiographic cVSP; occurs in 20 % to 40 % of
aSAH patients [15, 97]; only symptomatic cVSP, but not TCD or angiographic cVSP correlated
with DCI and mortality 3 months post aSAH [15]
Arterial narrowing on DSA not attributable to catheter-induced spasm or atherosclerosis [1];
occurs in up to 70 % of aSAH patients, indicating that angiographic cVSP can occur in the
absence of symptoms [1]; not all patients with angiographic cVSP experience DCI and vice
versa [21, 98]
Defined as a mean blood flow velocity in any vessel 9120 cm/sec, associated with symptomatic
or angiographic cVSP [99]
Defined as the presence of new infarction on hCT or MRI when the cause is felt to be
attributable to cVSP; is primarily a clinical diagnosis, because it does not require DSA
evidence of cVSP [3, 15]

Angiographic cVSP

TCD cVSP
Delayed cerebral
ischemia (DCI)

*Shown are clinically relevant definitions of cVSP and DCI, which were recently adopted into aSAH clinical practice guidelines and research [15].

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Pathophysiology of cVSP
The underlying pathophysiologic mechanisms of cVSP remain poorly understood, but appear to be multifactorial.

Does SAH cause cVSP?

Extensive basic and clinical research studies have attempted to validate this
causal relationship. Initial animal studies had suggested that blood products
from the SAH may cause cVSP [3, 23]. This theory was indirectly supported in
an animal model [24] and a small human study in which removing the clot
resulted in cVSP prevention. This, however, awaits validation in larger studies
[25]. Hematoma location, volume, duration of presence, and density have all
been shown to be independently associated with angiographic cVSP [3, 26,
27], however, without proving causation.

What causes cVSP?

Several mechanisms may be responsible for the development of cVSP.

Hemoglobin (Hb) and cVSP

Strong evidence exists from in vivo and in vitro studies that the release of
oxyHb from the lysis of subarachnoid red blood cells is present in high
concentrations in the cerebral spinal fluid (CSF) during the cVSP period.
OxyHb acts as a spasmogen and may be a key mechanism responsible for
cVSP [2, 28]. In addition, superoxide free radicals are released during autoxidation of Hb and may directly or indirectly cause vasoconstriction [2,
28]. Despite the extensive body of research, there is no general theory that
can explain the role of the Hbs in all the events that lead to cVSP. This raises
the hypothesis that the presence of Hb in the subarachnoid space may influence the arterial vasodilatory response by causing multiple, multifaceted
interactions with endothelium, neuron or smooth muscle cells [2].

Alternative proposed mechanisms for cVSP

Nitric oxide (NO) pathway
Endothelial NO (eNO) is an endogenous signaling molecule which directly acts on vascular smooth cells causing vascular relaxation [2].
An altered NO pathway due to scavenging by Hb in the cisternal space or
dysfunction of eNO synthase (eNOS) has been proposed to play an essential pathophysiological role in the development of cVSP [2]. Therapeutic intervention in a rat model with 17b-estradiol benzoate (E2)
activating the estrogen receptor subtype A (ERa) was reported to attenuate cVSP and preserve the eNOS expression [29]. Vasodilators with
pharmacological actions involving the NO pathway, nitrite [30] and

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sildenafil [31], have recently been studied with promising early safety
results. Phase II trials of both medications are ongoing.

Hypoxia Inducible Factor-1 (HIF-1)

Is a transcription factor that plays a key pathophysiological role in oxygen
homeostasis and adaptive responses to hypoxia and oxidative stress. HIF-1
regulates more than 40 identified genes including erythropoietin, BNIP3,
vascular endothelial growth factor (VEGF) and glucose transporter-1[32]. In
animal studies, HIF-1 has been shown to possibly cause vasoconstriction
within 24 hours and vasorelaxation at ~7 days after SAH [33]. This led to the
hypothesis that the role of HIF-1 may be harmful in the early stage and
neuroprotective at a later stage after SAH [33, 34]. HIF-1s early pro-death
and late pro-survival role remains under investigation.

Endothelin pathway
Elevated levels of endothelin have been found in the CSF of aSAH patients
[35, 36]. Endothelin-1 is a potent vascular smooth muscle cells vasoconstrictor, and acts on two specific receptors, ET(A) and ET(B). Activation of
ET(A) and ET (B2) receptors on the vascular smooth muscle cells results in
vasoconstriction, whereas activation of ET(B1) receptor subtype, expressed
on the vascular endothelial cells, causes vasorelaxation [37] .
Preclinical and early phase clinical prophylactic treatment with clazosentan,
an ET-1 antagonist, were promising in limiting cVSP, but two recent Phase III
trials did not improve 90-day clinical outcomes [38].

Thrombin
A serine protease is a coagulation protein produced in blood clots; it binds to
fibrin and gradually releases from the clot. Rat models of intracerebral hemorrhage and ischemic stroke illustrated a role of thrombin in pathogenesis of
cerebral edema and blood brain barrier permeability [39]. Human studies
showed a correlation between the increased thrombin activity in patients CSF
and the degree of SAH and cVSP [40]. To further evaluate the relationship
between thrombin and cVSP, the role of antithrombin III was studied in a
rabbit model. Antithrombin III inhibited thrombin activity and attenuated
cVSP [41]. These studies highlight the possible neuroprotective role of
antithombin III and the need for future studies.

Inflammation
Pro-inflammatory cascades involving IL-6 have been shown to be critical
in the development and maintenance of cVSP after SAH [42, 43]. Leukocytes contribute the complex pathophysiology of cVSP through multiple potential pathways, primarily by causing free-radical induced
endothelial dysfunction [44] and significant vascular effects by leukotrienes, ET-1 and possibly consumption of NO [45].
Anti-inflammatory medications such as simvastatin have resulted in decreased perivascular migration of granulocytes as well as cVSP attenuation in
a rabbit model within 72 hours after SAH [46]. Several Phase II studies with
statins have shown safety and a promising efficacy signal in preventing cVSP
after aSAH [47]. The results of an ongoing Phase III trial (STASH) are eagerly
awaited [48]. Further studies are needed to validate the new theories, eluci-

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date the time course and evaluate the optimal time windows for treatment
targeting the inflammatory reactions and oxidative stress after SAH.

Pathophysiology in TBI-related cVSP

Several mechanisms that are alternatives from the aSAH mechanisms have been
proposed to account for the pathophysiology of cVSP secondary to tSAH.

Extravascular blood products causing a decrease

in vessel caliber
Few studies have proposed the correlation between quantity of blood in
the subarachnoid cisterns and risk of cVSP following tSAH [8, 49, 50].

Stretch injury from blast

Mechanical alteration of the cerebral blood vessels, through either direct
impact or stretch, has been implicated in blast-related cVSP in the absence of SAH [13, 14]. In vitro studies have supported this theory and
revealed that blast injury can trigger cVSP by distinct mechanics resulting
in vascular smooth muscle hypercontractility [51].

Alternative causes for DCI

The tSAH has been noted to have distinctly different patterns of DCI on hCT,
rarely correlating with vascular territories [10, 52]. In tSAH, cVSP may not play
a large role in the clinical deterioration of TBI patients, possibly because the
majority of the injuries may be explained by contusions and direct impact
[10, 13]. At the same time, the pattern of SAH in tSAH appears to differ from
that in aSAH, occurring more in the tentorial region with a more diffuse type
of hemorrhage [10]. This suggests different mechanisms of DCI in TBI. They
are either caused by small-vessel cVSP or a phenomenon called spreading
depression depolarizations [53, 54]. This rapid and nearly complete depolarization of a sizable population of brain cells with massive redistribution
of ions between intracellular and extracellular compartments propagates
slowly as a wave in brain tissue and results in ischemia. In animal and small
human studies after TBI and aSAH, such spreading ischemia has been independently associated with DCI and worse clinical outcomes [55, 56].

CVSP surveillance
Transcranial Doppler (TCD)
Is a noninvasive, inexpensive, rapid, and portable diagnostic tool. It provides immediate clinical information about cerebral blood flow velocities,
and thereby indirectly about vessel diameter. It has become the most widely
used technique in the neurocritical care unit for evaluating cVSP [57]. In a
meta-analysis, TCD reliably predicted proximal middle cerebral
artery (MCA) cVSP in 97 % of SAH patients. Despite its high
specificity (99 %) it has limited sensitivity (67 %). However, the

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combination of the Spasm Index (TCD velocity/hemispheric cerebral blood
flow [CBF]) [58] and the Lindegaard ratio (mean middle cerebral artery flow
velocity/mean extracranial internal carotid artery flow velocity) [59] increased
the sensitivity of TCD to detect clinical cVSP to 85 % [18]. Disadvantages of
TCD include its operator dependence with limited ability to obtain consistent
measurements in distal skull base arteries and decreased utility in the evaluation of the anterior and posterior cerebral territories [60].

Cerebral arteriogram (DSA)

Remains the gold standard for the diagnosis of cVSP due to its high resolution
and real-time imaging. In addition, it offers the benefit of endovascular treatment.

CT angiography (CTA)
has become the first-line modality in the identification of cVSP due to its
availability. The image quality can be limited by motion artifact and the
technique of dye administration. CTA in general tends to overestimate the
size of larger blood vessels, which creates an over-accentuation of cVSP [60].

CT perfusion (CTP)
scanning has increasing diagnostic utility [61]. A recent prospective study on
CTP has validated the sensitivity of CBF (93 %) and mean transit time (MTT)
(88 %) in diagnosing DCI [62]. CTP could be a valuable tool in evaluating
distal vasculature and functional perfusion compared to DSA and CTA, which
are less accurate in evaluating smaller distal vessels . In a recent study, CTP
specificity to detect cVSP was 990 %, when it was done within 3 days after SAH,
with noticeable prolongation of MTT and decrease in CBF on the baseline test
[62]. These findings possibly suggest the utility of CTP as a future technique for
an early prediction of DCI but further validation is warranted.

Perfusion-weighted MRI
This imaging modality may reveal small regions of early ischemic insults, indicating territories suffering from severe cVSP [63]. Its limitations include the
usual limitations for MRI, including the need for transport, and prolonged
imaging time, thereby excluding many critically ill and high-risk patients.

Other imaging modalities

At this point, there are several other techniques, including single-photon
emission computed tomography (SPECT), positron emission tomography (PET) and xenon-enhanced CT (Xe-CT), which are available for
evaluation of brain tissue perfusion distal to the large intracranial vessels,
but are not widely available.

Continuous brain tissue monitoring

Continuous EEG (cEEG) monitoring
Is currently a widely used monitoring modality for several reasons. Its
high sensitivity was shown in one prospective study in which decreases

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in alpha wave activity had 100 % sensitivity detecting cVSP almost 3 days
earlier than TCD or DSA [64]. It has an additional benefit for diagnosing
subclinical seizures in patients with an unreliable exam. Lastly, cEEG can
differentiate cVSP from seizure activity. Although it does so with variable
reliability, quantitative analysis of cEEG suggested achieving such differentiation earlier than other non-continuous monitoring and imaging
modalities such as MRI or CT [65]. Limitations of cEEG include the vast
amount of data requiring real-time analysis, and the labor associated
with the analysis and process of applying electrodes.

Brain tissue oxygen (PbtO2) monitoring

Requires the implantation of a probe in a region at risk for cVSP and provides local brain tissue oxygenation data about changes in the surrounding
microenvironment at repeated time intervals. Small studies showed a strong
association between PbtO2 and cVSP [66]. A different study of 67 aSAH
patients suggested that PbtO2 pressure reactivity is a reliable indicator of
impaired autoregulation and cVSP [67]. These new findings questioned the
reliability of this invasive monitoring technique in cVSP monitoring, given
that it only provides information about local brain tissue oxygenation, and
may miss other brain areas at risk for DCI [68].

Cerebral microdialysis
Is capable of measuring local levels of various interstitial cerebral metabolic markers including glutamate, lactate, pyruvate, and glucose, and
can signify changes in values in areas undergoing DCI [69]. Microdialysis
has been shown to be 89 % specific for ischemia, before a patient becomes symptomatic, by detecting changes in glucose, lactate and glutamate [70]. In another SAH study, higher levels of microdialysis measured
cerebral markers taurine, lactate and nitrite that were found to be associated with poor neurologic outcome [71]. The limitations of this technique, similar to PbtO2 monitoring, are that in addition to being
invasive, information can only be gathered about a small region in the
brain. Therefore, it has limited sensitivity in a condition that can have
regional or global effects.

Continuous CBF measurement using thermal diffusion

Via a brain tissue thermal diffusion probe can detect DCI and cVSP early
[72]. Similar to PbtO2 monitoring and microdialysis, a thermal diffusion
probe may be inserted into the brain via a burr hole into the white
matter of a region deemed to be at risk for ischemia. In small study of 14
patients with high grade SAH, thermal diffusion was more reliable than
TCD in detecting symptomatic cVSP. A regional CBF of 15 mg/100 g/min
was identified using a single probe as reliable for a cutoff that had 90 %
sensitivity and 75 % specificity for cVSP [72].

Jugular bulb oximetry

In this technique, an oxygen saturation probe is inserted into the
jugular vein above the facial vein; providing sampling from the
intracranial circulation and offering a global view of cerebral perfusion [73]. The cerebral oxygen extraction (CEO2 or AVDO2) can

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be measured by subtracting cerebral venous oxygen saturation from
the arterial oxygen saturation. A small study showed that AVDO2
increased 924 hours prior to the onset of symptomatic cVSP [74].
In the same study, symptom resolution was associated with significant improvement in AVDO2 after initiating cVSP therapy (hypertensive, hemodilutional, and hypervolemic therapy) in these
patients [74].

Treatment of cVSP
Calcium channel blocker
Nimodipine is a dihydropyridine calcium antagonist that blocks calcium
influx through L-type calcium channels and has selectivity for vascular
smooth muscle. Oral nimodipine has become standard therapy in the setting of aSAH after several randomized trials have demonstrated improved
outcomes and secondary ischemia [75, 76]. Importantly, it does not significantly prevent or reverse angiographic cVSP [76]. A recent comprehensive
meta-analysis suggested that the improvement in neurological outcomes
could be secondary to alternative mechanisms other than large-vessel
narrowing, including pial collateral circulation augmentation, decreased
small vessel resistance and neuroprotection role via reduction of calciummediated excitotoxicity [75].

Dantrolene
The continuous elevation of intracellular Ca2+-levels required for vasoconstriction is achieved by a combination of influx from extracellular Ca2+
(inhibited by nimodipine), and released from the largest intracellular Ca2+
store, the endo/sarcoplasmatic reticulum mediated by the ryanodine receptor (RyR) [77, 78]. Dantrolene is a known RyR inhibitor and is US Food
and Drug Administration approved for malignant hyperthermia and spasticity. Dantrolene has been shown to be neuroprotective in many animal
models of various neurological diseases [79, 80]. More cVSP specific investigations have revealed that dantrolene inhibits cerebral vasoconstriction
alone as well as in combination with nimodipine in an ex-vivo rat model
[81]. Two small human studies of single IV-dantrolene doses have suggested
that dantrolene may attenuate cVSP after SAH [82, 83]. In addition,
dantrolene given intra-arterially during angiography has been reported to
improve refractory cVSP [84]. Results from a single-center feasibility study of
repeated IV-dantrolene doses in aSAH patients should result soon [85].
Combining L-type specific Ca2+-channel blockers with a RyR blocker may be
an important therapeutic target in cVSP.

Hemodynamic augmentation
Traditionally described as Triple H-therapy (hypervolemia, hypertension,
hemodilution), it aims to increase cerebral perfusion. However, despite its
widespread use as a mainstay therapy for cVSP, there are no randomized
control trials to support this intervention [1, 86]. Prophylactic

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hypervolemic therapy alone after surgical repair of the ruptured aneurysm
has been studied in randomized controlled trials. While no benefit was
shown for cVSP, CBF, or clinical outcome, these studies revealed that
hypervolemia resulted in pulmonary edema, as well as hemodilution and
with it a decrease in arterial oxygen and oxygen carrying capacity [87].
Anemia has been associated with a worse outcome after aSAH [88]. These
studies achieved the elimination of hemodilution from Triple-H-therapy,
leaving HHT (hypervolemic, hypertensive therapy) as the mainstay in
clinical practice, as recommended in the American Heart Association and
Neurocritical Care Society SAH guidelines [1, 20].

Endovascular management of DCI

Optimal timing and method of endovascular rescue therapy is unclear. Ideally, endovascular treatment should be considered in patients at risk for cVSP-related ischemic prior to the development of
DCI. The literature on this intervention is limited to very few prospective studies. The feasibility and safety profile of angioplasty,
intra-arterial vasodilator therapy and the combination of both was
demonstrated in previous studies [20]. Nevertheless, there is no
clear data about the superiority of any of these interventions to one
another, alone or in combination, or to medical treatment alone that
have been previously validated [20]. Prophylactic angioplasty done
in patients without the presence of angiographic arterial narrowing
exposed patients to risk of vessel rupture and death without clear
benefit in outcome [89]. Thus, routine prophylactic cerebral angioplasty is not recommended in the NCC guidelines. More vital information about the timing, duration and optimal number of the
endovascular rescue therapy is still needed and necessitate more exploration.

Statins
Have been studied in several small, single-center randomized trials
with variable results. Although a recent meta-analysis of four Phase II
trials suggested no evidence for clinical benefit [90], results from a
phase III trial (Simvastatin in Aneurysmal Subarachnoid Hemorrhage
STASH) are eagerly awaited [48]. The current NCS SAH guidelines
recommend continuation of statins in patients who are on them
prior to aSAH [20].

Clazosentan
Is an endothelin-1 receptor antagonist and had been shown in a
phase IIb trial (Clazosentan to Overcome Neurological iSChemia and
Infarct Occurring after Subarachnoid hemorrhage CONSCIOUS-1) to
be associated with a dose-dependent reduction in the incidence of
angiographic cVSP [91]. In two subsequent phase III trials there was
no improvement found in 90-day functional outcome in the
clazosentan group [92, 93].

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Magnesium sulfate
Is a non-competitive calcium channel blocker with vascular and neuroprotective effects. It has been studied in several pilot trials which suggested some of reduction in DCI associated with magnesium infusion,
however, there was no benefit shown in a phase III trial (Intravenous
Magnesium sulfate for Aneurysmal Subarachnoid Hemorrhage IMASH)
[94]. The 2011 NCS guideline does not recommend induced
hypermagnesemia [20].

Treatment of TBI-related cVSP

Management of cVSP in tSAH presents challenges distinct from the ones encountered in aSAH. Treatments usually used in aSAH related cVSP such as
nimodipine and HHT could be detrimental in the setting of TBI, depending
on the severity of injury and associated comorbidities. HHT may worsen cerebral edema from hypertension and increased perfusion in states of poor
autoregulation [95], which is common in TBI. In addition, hypertension
may increase the bleeding risk systemically in the aforementioned and in
the brain. Calcium-channel blockers can negatively affect cerebral perfusion
and intracranial pressures. Undesirable effects of low CBF in the setting of hypotension are particularly worrisome in TBI patients as cerebral hypoperfusion is a prominent cause of secondary brain insult [96]. Finally, a pooled
analysis of four studies comparing calcium-channel blocker therapy to placebo in tSAH patients showed no difference in mortality or poor outcome [97].
Therefore, TBI-related cVSP is usually treated with endovascular therapy without the use of nimodipine or HHT.

Conclusions
For the past decades, the understanding of cVSP has evolved to explore new
complex biochemical cascades. We have revealed commonalities and differences in aSAH and TBI-related cVSP. The extensive research summarized here
has identified promising new therapeutic targets.

Compliance with Ethics Guidelines

Conflict of Interest
Susanne Muehlschlegel has received grant support from the American Heart Association.
Saef Izzy declares that he has no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with animal subjects performed by any of the authors. With regard to
the authors research cited in this paper, all procedures were followed in accordance with the ethical standards of
the responsible committee on human experimentation and with the Helsinki Declaration of 1975, as revised in
2000 and 2008.

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