Cerebral vasospasm following subarachnoid hemorrhage
(SAH): physiopathology, diagnosis and current management.
Critical review of literature.
Paulo Henrique Pires de Aguiar1 MD,PhD, Antônio Santos de Araújo Júnior2,
Mirella Martins Fazzito3, Renata Simms4,5, Miguel Melgar6 MD, Andrea
Kleindienst7
1- Department of Neurology, Sao Paulo Medical School, São Paulo, Brazil
2- Neurosurgeon from Sírio-Libanês Hospital, São Paulo, Brazil
3- Neurologist from Sirio-Libanês Hospital, São Paulo, Brazil
4- Neurologist from Sirio-Libanês Hospital, São Paulo, Brazil
5- Neurologist from Santa Paula Hospital, São Paulo, Brazil
6- Department of Neurological Surgery of Tulane University, New Orleans
Louisiania, United States
7- Department of Neurosurgery, St Marien Hospital Amberg, University of
Erlangen-Nuremberg, Germany
Key words: cerebral vasospasm, subarachnoid hemorrhage, smooth muscle
cells, brain aneurysm
ABSTRACT
The cerebral vasospasm and the delayed cerebral ischemia remain a
source
of
substantial
morbidity
and
mortality
following
aneurysmal
subarachnoid hemorrhage (SAH).
Hemodynamic manipulation better known as ‘triple H’ therapy is
routinely used in the management of patients with acute vasospasm following
subarachnoid
hemorrhage.
The
rationale
of
inducing
hypertension,
hypervolemia and hemodilution is to improve blood flow to the injured brain
and prevent secondary ischemia.
While the Ca2+ antagonist Nimodipine is still the only drug with proven
benefit on neurologic outcome following SAH, several alternatives are under
research.
Tirilazad is not effective, and studies of hemodynamic maneuvers,
magnesium, statin medications, endothelin antagonists, steroid drugs,
anticoagulant/antiplatelet agents, and intrathecal fibrinolytic drugs have
yielded inconclusive and controversial results
Steroids drugs and anticoagulant/antiplatelet agents have been
abandoned so far because of the lack of efficacy. The purpose of the present
paper is to provide a systematic review of the existing literature on the
treatment of cerebral vasospasm.
2
RESUMO
O vasoespasmo cerebral e a isquemia cerebral tardia respondem de
maneira substancial para a morbidade e mortalidade da hemorragia
subaracnóide (HSA) de etiologia aneurismática.
A terapia hemodinâmica, mais conhecida como “três-H”, é usada
rotineiramente no manejo dos pacientes com vasoespasmo secundário à
HSA. A razão de se induzir hipertensão relativa, hipervolemia e hemodiluição
nestes doentes é melhorar o fluxo sanguíneo cerebral e evitar a isquemia
tardia.
Atualmente, apenas o bloqueador de canal de Calcio Nimodipina tem
benefício comprovado no tratamento do vasoespasmo na HSA.
Várias outras alternativas estão sendo estudadas. O Tirilazad não é
efetivo, e vários outros têm resultados contoversos, tais como: sufato de
magnésio, estatinas, antagonistas de endotelina, esteróides, antiagregantes
plaquetários, e fibrinolíticos intratecais.
O objetivo deste trabalho é promover uma revisão sistemática da
literatura existente acerca do tratamento do vasoespasmo cerebral.
Palavras-chave:
vasoespasmo
cerebral,
hemorragia
subaracnóide,
aneurisma cerebral
3
INTRODUCTION
Aneurysmal subarachnoid hemorrhage (SAH) is related with a mortality
of about 50%. In addition to the hazards of a second hemorrhage, vasospasm
contributes substantially to secondary brain damage and post-operative
stroke. Vasospasm refers to a contraction of smooth muscle cells in the wall
of cerebral arteries. However, the pathophysiology is not well understood.
This article reviews the existing literature on this important topic in
vascular neurosurgery and highlights some of the most recent findings and
treatment options.
DEFINITION
The term "cerebral vasospasm" is commonly used to refer to the
combination of a delayed onset of ischemic neurological deficits following
aneurysmal SAH ("symptomatic vasospasm") and the narrowing of cerebral
vessels documented by angiography or other vessels documented by
angiography or other studies ("angiographic or arterial vasospasm") (Figure
1). Arterial vasospasm typically appears 3 to 4 days after rupture and reaches
a peak incidence and severity at 7 to 10 days 1.
Figure 1: Angiographic vasospasm in aneurysm of middle cerebral artery
(lateral angiographic view).
4
EPIDEMIOLOGY
The incidence and time course of symptomatic vasospasm parallels
that of arterial vasospasm. However, while in 40% to 70% of patients arterial
narrowing is evident – as documented by angiography or transcranial doppler
sonography, only 20% to 30% develop the clinical symptoms. The most
important factors determining the clinical effect of arterial vasospasm are the
severity and extent of vessel narrowing. Symptomatic vasospasm typically
begins 4 to 5 days after SAH, and is characterized by the insidious onset of
confusion and a decreasing level of consciousness. When the arterial
narrowing is pronounced, these symptoms may progress to focal neurological
deficits, infarction, coma and death. In less severe cases, neurological
recovery can be expected as soon as the arterial narrowing resolves 1.
Cerebral vasospasm will develop in more than half of SAH patients,
and symptomatic vasospasm will occur in approximately one-third, which is
associated with neurologic symptoms of ischemia 2.
According to a demographic study at the University of Mississippi, 1993
to 1999, patients with symptomatic vasospasm have a high prevalence of preexisting chronic morbidity. 75% of patients have a known medical history of
either hypertension or diabetes, or both. While the mortality in African
American and Caucasian male did not differ significantly, it was statistically
higher than in the combined female groups 3.
A systemic review of untreated unruptured cerebral aneurysms (UCA)
in Japan showed that the risk of rupture is significantly higher than that
reported by a large-scale North American and European cohort studies 4. This
difference in the rupture risk may result from differences in the racial or
5
genetic background, although a study bias may be evident. Morita et al
conclude that untreated UCAs in Japan may have a significantly higher rate of
rupture 4. These findings can partially explain an excessive number of SAH
and vasospasm in Japan.
Female gender is a significant risk factor determining the onset of
vasospasm following SAH, and may be as high as 1:9 according to the
casuistic study of Quinn et al 5. However it has to be considered that there
exists a female predominance among patients with aneurysmal SAH
6,7.
The
approximated male to female ratio has been reported as 1:2 8, with a similar
mortality ratio 9. Hormonal changes due to menopause have been proposed
as an explanation for gender differences 10,11. Recent research has advocated
that hormone replacement therapy may have a protective role against SAH.
The decline of estrogen levels during and after menopause may result in a
decreased collagen content within arterial vessel walls, and hence predispose
to aneurysm formation 12.
Based on a recent study in West Yorkshire, with 100 cases of
aneurysmal SAH cases per year among a population of 2.5 million, the mean
age of patients with SAH was 51 years, both in male and female, while within
the vasospasm group, the mean age was 49 years 5.
With respect to the total vasospasm group, half progress to cerebral
infarction and half recover without deficit. However, it is important to recognize
that angiographic findings may not correlate with the patient's clinical
presentation 13. Several factors are associated with the risk of ischemia: large
volume of initial SAH, dehydration, use of antifibrinolytic agents, arterial
hypotension, increased intracranial pressure, and reduced oxygen delivery 2.
6
Furthermore, in the past decades studies demonstrated risk factors for the
development of vasospasm: thickness of blood clot on the initial cranial
computed tomography (CT), early increase in transcranial Doppler flow
velocities, Glasgow coma score < 15, presence of a carotid or anterior
cerebral artery aneurysm, age < 50 years, good neurological grade (World
Federation of Neurological Surgeons (WFNS) grade 1 and 2) and
hyperglycemia 14,15,16.
Applying the WFNS grading scale in a study of 1635 SAH patients in
Europe, Australia, New Zealand, South Africa and North America 1991 to
1997, an unfavorable outcome due to vasospasm occurred in 13% WFNS 1,
20% WFNS 2, 42 % WFNS 3, 51% WFNS 4 and 68% WFNS 5 17.
An unfortunate case is shown to emphasize the poor outcome that
vasospasm secondary to subarachnoid hemorrhage may develop (Figure 2).
Figure 2: A 54-year-old female patient with SAH. The angiography (A) shows
and anterior communicating artery aneurysm, and the TC scan (B) shows a
hemocistern grade IV (Fisher Grade). After clipping, the patient developed a
severe vasospasm confirmed clinically and by Transcranial Doppler, and was
undergone a decompressive craniectomy (C).
7
PHYSIOPATHOLOGY
General aspects
Arterial vasospasm most likely involves alterations in the structure of
the vessel wall resulting from prolonged smooth muscle contraction.
Hypertrophy, fibrosis, and degeneration as well as inflammatory changes in
the vessel wall are secondary delayed effects. Extensive research
demonstrated the event initiating the cascade resulting in vasospasm is the
release of the blood breakdown product oxyhemoglobin
18.
However, the exact mechanism by which oxyhemoglobin induces
vasocontriction is unknown. The multifactorial process involves the generation
of free radicals, lipid peroxidation, and activation of protein kinase C as well
as phospholipase C and A2 with subsequent accumulation of diacylglycerol
and the release of endothelin-1. These events create a positive feedback loop
that, in turn, produces a tonic state of smooth muscle contraction and
inhibition of endothelium-dependent relaxation 1.
Calcium
Sasahara et al, 2008, used a genome-wide canine oligonucleotide
microarray analyses to investigate alterations in gene expression on day 7 in
a double SAH model. A decrease in vessel caliber of basilar arteries was
accompanied by an up- and down-regulation of diverse genes. Network
analyses demonstrated a significant association with molecules belonging to
Ca2+ cell signaling and the p38 MAPK stress response pathway. Although
the approach chosen may have documented late-stage changes of the
8
disease process rather than early, disease-causing pathomechanisms, the
results support an important role for intracellular Ca2+ homeostasis 19.
Constriction of small (100-200 µm diameter) cerebral arteries in
response to increased intravascular pressure plays an important role in the
regulation of cerebral blood flow. In cerebral arteries from healthy animals,
these pressure-induced constrictions arise from depolarization of vascular
smooth muscle leading to enhanced activity of L-type voltage-dependent
calcium channels. Enhanced pressure-induced constrictions and the resulting
decrease in cerebral blood flow may contribute to the development of
neurological deficits in SAH patients following cerebral aneurysm rupture.
Thus, small diameter arteries may represent important targets for current
treatment modalities (e.g. Hypertensive, Hypervolemic, Hemodilution \ "triple
H" therapy) used in SAH patients.
Potassium (K+) Channels
Smooth muscle contraction, and thus arterial diameter, is influenced by
the membrane potential, which is determined by the K+ conductance.
Voltage-gated (Kv) and large-conductance, Ca2+-activated K+ channels
dominate in arterial smooth muscle K+ conductance. Vasospastic smooth
muscle cells are depolarized relative to normal cells, and it has been
hypothesized that K+ channels may be involved in this imbalance. However,
Jahromi et al, 2008 demonstrated following SAH in the dog that there were
no significant differences in Ca2+-activated K+ current density, kinetics, Ca2+
and voltage sensitivity, single-channel conductance or apparent Ca2+ affinity
between normal and vasospastic basilar-artery myocytes. Had no, small- or
9
intermediate-conductance, Ca2+-activated K+ channels
20.
conductances
depolarization
may
underlie
the
membrane
Hence, other ionic
and
vasoconstriction observed during vasospasm after SAH.
Nitric Oxide
Nitric oxide (NO) is produced by the endothelial NO synthase (eNOS)
in the intima and by the neuronal NO synthase (nNOS) in the adventitia of
cerebral vessels. By activating soluble guanylyl cyclase, NO increases the
production of 3-5cGMP, which relaxes smooth muscle cells and dilates the
arteries in response to shear stress, metabolic demands and changes of pCO
(chemoregulation). 3-5cGMP is then metabolized by phosphodiesterases
(PDEs). Following aneurysmal SAH, this regulation of cerebral blood flow
(CBF) is disturbed. It has been speculated that oxyhemoglobin, gradually
released from erythrocytes in the subarachnoid space surrounding the
conductive arteries, destroys nNOS-containing neurons and thereby deprives
the arteries of NO. A transient eNOS dysfunction evoked by increased levels
of the endogenous NOS inhibitor, asymmetric dimethylarginine (ADMA) in
cerebrospinal fluid (CSF) in response to the presence of bilirubin-oxidized
fragments, prevents reactive vasodilation. This eNOS dysfunction sustains
vasospasm until ADMA CSF levels decrease and NO release from endothelial
cells increases. Thus, exogenous delivery of NO has been speculated to
provide a therapeutic modality to prevent and treat vasospasm
21,22.
Inflammation
10
Some studies indicate that inflammation plays a putative role in
cerebral vasospasm after SAH. C-Jun N-terminal kinase (JNK), a member of
the mitogen-activated protein kinase group, has been shown to be involved in
the response to a variety of extracellular stresses and has been implicated in
numerous physiological processes including inflammation. SP600125, an
inhibitor
of
the
JNK
signaling
pathway
reduced
angiographic
and
morphological vasospasm in the basilar artery of dogs following SAH 23.
Endothelin
Increased levels of endothelin-1 (ET-1), one of the most potent
endogenous vasoconstrictors, have been suggested to play a role in cerebral
vasospasm. The synthesis of ET-1 by endothelial cells is activated by
physicochemical factors such as shear stress, hypoxia, and elevated oxidized
low-density
lipoproteins.
These
stimuli
may
trigger
ET-1–mediated
vasospasm, although the exact intracellular signaling mechanisms are not yet
fully understood. Effects of the selective endothelin A receptor antagonist
Clazosentan on cerebral perfusion and cerebral oxygenation following severe
SAH has been investigated in phase II trial
24.
At the moment, a randomized,
double-blind, placebo-controlled, dose-finding study assesses the efficacy and
safety of intravenous clazosentan following SAH 25.
Protein Kinase
About 30 years ago, protein kinase C (PKC) has been discovered and
its pathophysiological functions remain a subject of great interest. Beside its
role as ubiquitary second messenger in receptor signaling, PKC plays a role
11
in the regulation of the myogenic tone
26.
PKC may directly amplify vascular
reacticity to different agonists, but may also interact with other signaling
pathways as myosin light chain kinase, NO, intracellular Ca2+, protein
tyrosine kinase (PTK) and its substrates such as mitogen-activated protein
kinase (MAPK). The role of PTK and MAPK in cerebral vasospasm has been
investigated with some vigor.
PTK regulates Ca2+ signaling, especially Ca2+ entry, and PTK
antagonists Ca2+ release from internal stores and Ca2+ entry, and probably
through this action its relaxant effect on cerebral arteries is mediated 27.
MAPK is activated following experimental SAH, and as a dual substrate to
serine/threonine kinase and PTK it may serve as a “common pathway” to
relay signals. Accordingly, MAPK inhibitors reduced cerebral vasospasm
following experimental SAH 28,29,30,31.
DIAGNOSIS
In the diagnosis of cerebral vasospasm, it is recommended to follow
the patient closely for clinical signs of vasospasm correlating them with daily
transcranial doppler (TCD) sonography. Associated with vasospasm,
hyponatremia may occur and has to be ruled out by checking serum
electrolytes repeatedly.
Several factors may increase the risk of vasospasm-related ischemia;
these include large volume of initial SAH, dehydration, use of antifibrinolytic
12
agents, arterial hypotension, increased intracranial pressure, and reduced
oxygen delivery 13.
Transcranial Doppler sonography
A daily TCD examination performed by an experienced person should
be used routinely to provide early identification of patients at high risk for
vasospasm (Figure 3, 4 and 5). A clinical study, comparing angiography,
clinical findings and TCD in diagnosis of cerebral vasospasm, calculated by
the receiver operating characteristics analysis TCD threshold of 100 cm/s to
detect angiographic vasospasm, and of 160 cm/s to detect clinical vasospasm
32
(Figure 6).
Figure 3: Principle of sonation used in TCD in order to reach the sound of
arterial pulse in depth through a bone window.
Figure 4: Portable ultrasound for TCD (Fukuda, Denshi, Japan)
Figure 5: During the exam of TCD, the ultrasound sensor is handled by the
observer over the temporal side, frontal and orbit. Multimodal monitoring may
be useful to treat and control vasospasm.
Figure 6: Velocity of cerebral flow visible and measured through TCD
13
Cerebrovascular responses to variations in blood pressure and CO2
are attenuated during vasospasm after SAH. However, cerebral blood flow
velocities (CBF-V) as measured by TCD may not necessarily reflect cerebral
blood flow (CBF). While in controls, pCO2 levels were correlated with both
CBF-V (r = 0.94, p < 0.001) and CBF (r = 0.87, p = 0.005), in vasospasm
CBF-V was correlated with pCO2 (r = 0.54, p = 0.04) but CBF was not (r = 0.09, p = 0.83). Thus, in the presence of vasospasm, but blood flow velocities
as measured by TCD do not necessarily reflect CBF
33.
In a series of 18 patients with vasospasm after SAH (Hunt&Hess III-IV),
TCD indices were used to estimate the optimal arterial blood pressure in
hypervolemia/hypertension/hemodilution therapy. An increase in the CBF
index was associated with better performance on neurologic examination
34.
However, comparing the cerebral perfusion pressure (CPP) estimated from
TCD analysis with CPP derived from direct measurement of intracranial
pressure, there was no correlation ( = 0.15, p = 0.26) 34.
In 15 patients with clinical vasospasm, the critical closing pressure
(CCP), was measured by two different TCD methods (Aaslid and Michel).
Soehle et al showed that CCP decreased significantly (p<0.05) during
vasospasm (CCPAaslid=6.3±22.9 mm Hg, CCPMichel=14.9±16.5 mm Hg,
mean±SD) as compared with baseline (CCPAaslid=24.4±20.3 mm Hg,
CCPMichel=27.8±19.4 mm Hg). In addition, CCP was significantly lower on the
side of vasospasm (CCPAaslid=11.9±24.2 mm Hg, CCPMichel=18.4±19.6 mm
Hg)
as
compared
with
the
contralateral
nonvasospastic
(CCPAaslid=24.7±22.3 mm Hg, CCPMichel=28.2±18.0 mm Hg)
35.
side
Interestingly,
14
assuming vasospasm to increase vasomotor tone, opposite to these findings
an increase in CCP would have been expected. Alternatively, CCP might
have decreased during vasospasm because of a vasodilatation distal to the
spastic vessel. Thus, interpretation of CCP in vasospasm is difficult and may
be overshadowed by nonlinear hemodynamic effects.
Comparing younger (<68 years of age n=47) and older (≥68 years of
age n=34) patients following SAH, Torbey et al. found middle cerebral artery
(MCA) and internal carotid artery (ICA) mean flow velocity to be lower in older
patients (median 76 versus 114 cm/s and 76 versus 126 cm/s, respectively;
p<0.003). Older patients have a lower incidence of symptomatic vasospasm
(44% versus 66%; p=0.05), and such vasospasm develops at lower CBF-V
than in younger patients (MCA median 57 versus 103 cm/s; p=0.04 and ICA
median 54 versus 81 cm/s, P=0.02). A quadratic relationship was found
between age and CBF-V (p<0.0001) 36.
TREATMENT
General Considerations about the current treatment
The main goal of current treatment is to prevent arterial or limit the
severity of and symptomatic vasospasm. At the moment, two therapies are
generally accepted to be of substantial value in reducing the ischemic
complications related to vasospasm: treatment with cerebroselective calcium
channel blocker nimodipine
(Nimotop®) to
reverse
vasospasm
and
hypervolemic, hypertensive hemodilution to elevate the CPP and thus provide
15
blood to regions of the brain with marginal perfusion because of arterial
spasm.
CLINICAL TREATMENT
“Triple-H” treatment
The efficacy of the "triple-H" therapy (hypertension, hypervolemia, and
hemodilution) for cerebral vasospasm has not been demonstrated in
controlled clinical trials
37,38,39.
Nevertheless, several uncontrolled studies
indicate that this treatment may aid in the resolution of deficits caused by
vasospasm. Triple-H therapy is associated with significant risk, which includes
heart failure, electrolyte imbalance, cerebral edema, and potential aneurysmal
rupture, and therefore patients usually receive intensive care monitoring.
Triple-H therapy is recommended for preventing and treating ischemic
complications from vasospasm, with the aneurysm to be clipped surgically
when possible. While transcranial cerebral oximetry seems to be of limited
value for the detection of vasospasm, it may be useful in estimating the
clinical impact of triple-H therapy in such patients 40.
A considerable variation exists regarding fluid management and the
use of vasopressors and inotropes. Blood pressure augmentation, volume
expansion and cardiac contractility enhancement may improve CBF in
ischemic areas, ameliorate vasospasm and improve clinical condition
41.
High
doses of catecholamines may cause adverse adrenergic effects. Alternatively,
Arginine vasopressin (AVP), which has been shown to stabilize advanced
16
shock states while facilitating reduction of catecholamine doses, its use may
be considered as an alternative supplementary vasopressor in SAH
42.
The
limited data available suggest that low-dose AVP does not cause brain edema
42.
Beside volume replacement to induce moderate hypervolemia and
hypertension, taking always into concern the pulmonary previous condition,
avoiding fluid restriction is mandatory. Hemodilutition may result in
coagulation problems and can be discussed depending on ICP and cerebral
oximetry, and is therefore not an integral part of therapy in most centers.
Triple-H therapy may cause additional shear stress on unsecured
aneurysms, and is therefore associated with the risk of bleeding. Risk factors
for the association between triple-H therapy and dissecting aneurysms are
unclear, but the patients are often smokers and have hypocholesterolemia,
including low apolipoprotein E levels
43.
If these patients suffer SAH, the
management is complicated. A prophylactic obliteration during the early acute
stage of SAH may lead to better outcomes if the unruptured dissecting lesion
appears an obvious aneurysmal dilatation or pearl-and-string sign and is
safely treatable with endovascular trapping 43.
Calcium Antagonists
Nimodipine
17
The only drug in treatment of vasospasm improving outcome
considerably is Nimodipine, with a 40 to 86% reduction of vasospasm
44,45.
Guidelines from the AHA Stroke Council indicate that "oral nimodipine is
strongly recommended to reduce poor outcome related to vasospasm." These
guidelines indicate that the value of other calcium antagonists, whether
administered orally or intravenously, remains uncertain
44.
Decreased blood
pressure is the most common side effect, occurring in 4.4% of patients.
Therefore, blood pressure should be monitored continously. Other side
effects occurring at a low frequency of ≥1.0% include headache, nausea, and
bradycardia. No clinically significant effects on hematologic factors, renal or
hepatic function, or carbohydrate metabolism have been causally associated
with oral nimodipine, and Nimotop® does not appear to affect anesthetic
management 46.
A detailed review of 41 studies by Weyer et al in 2006 resulted in the
conclusion that the only proven therapy for vasospasm is nimodipine 47.
A previous meta–analysis of all published randomized trials on
prophylactic nimodipine included 1202 patients. Nimodipine was associated
with an improvement in the odds ratio of good and of good plus fair outcomes
by 1.9:1 and 1.7:1, respectively (p<0.005 for both measures). The odds ratio
of either deficit or mortality attributed to vasospasm and of cerebral infarction
on cranial computed tomography were reduced by 0.5:1 to 0.6:1 in the
nimodipine group (p<0.008 for all measures) 48.
Nicardipine
18
Local intra-arterial infusions of verapamil and nicardipine have also
been used to treat cerebral vasospasm. Only a few reports of early clinical
experience
and
limited
data
are available
regarding their cerebral
physiological activity. Lavine et al assessed the efficacy of intracarotid
administration of verapamil and nicardipine on augmenting cerebral blood flow
in New Zealand white rabbits. They compared the capability to reverse topical
endothelin (ET)-1-triggered vasospasm, and concluded that intra-arterially
administered nicardipine is a more potent cerebral vasodilator and is superior
to verapamil 49.
Recently
selective
intra-arterial
injection
of
nicardipine
during
angiography has also been proposed as a therapeutic modality for the
management of distal vasospasm not amenable to balloon angioplasty
50.
Systolic but not diastolic or mean arterial pressure decreased significantly
after the injection, can cause significant hemodynamic instability and requires
supportive management by an anesthesiologist 50.
Fasudil
Fasudil (Eril; Asahi Kasei Pharma Corp, Tokyo, Japan) is a potent Rhokinase inhibitor (Figure 7), and Fasudil hydrochloride (hexahydro-1-(5isoquinolinesulfonyl)-1H-1,4-diazepine hydrochloride, FH, AT877) has been
developed to treat vasospasm. In order to find an ideal dose for administration
of Fasudil in SAH, a daily dose of 20, 40, 60, 90 and 120-180 mg were
compared. AT877 was given by intravenous infusion over 30 min two or three
times a day for 14 days after surgery. Although AT877 did not completely
abolish angiographic vasospasm, severe vasospasm was less frequent
19
following higher doses
51.
Only mild hypotension was seen. Part of its effect
may be attributable to protection of the brain from ischaemic insults due to
chronic cerebral vasospasm 52.
A prospective randomized placebo-controlled double-blind trial of
Fasudil or AT877 was performed with the cooperation of 60 neurosurgical
centers in Japan
53.
267 patients, who underwent surgery within 3 days after
SAH, received either 30 mg AT877 or a placebo (saline) by intravenous
injection over 30 minutes, three times a day for 14 days. AT877 reduced
angiographically demonstrable vasospasm by 38% (from 61% in the placebo
group to 38%, p = 0.0023), low-density regions on computerized tomography
associated with vasospasm by 58% (from 38% to 16%, p = 0.0013), and
symptomatic vasospasm by 30% (from 50% to 35%, p = 0.0247).
Furthermore, AT877 reduced the number of patients with a poor clinical
outcome by 54% (from 26% to 12%, p = 0.0152
52.
Zhao et al, 2006 investigated the efficacy and safety of FH in a
randomized open trial with nimodipine as control including 72 patients who
underwent surgery following aneurysmal SAH (Hunt& Hess I to IV). For 14
days following surgery, patients got either 30 mg of FH iv over 30 minutes
three times a day or nimodipine 1 mg/hr iv. Neither the incidence of
symptomatic vasospasm, CT findings or recovery evaluated by the Glasgow
Outcome Scale was different between the FH or the nimodipine group.
However, applying a score for aphasia, upper and lower extremities, the
authors found FH to improve neurological deficits significantly more than
nimodipine 54.
20
Figure 7: Fasudil - 5-(1,4-diazepane-1-sulfonyl) isoquinoline
Ozagrel
Ozagrel is a thromboxane A2 synthase inhibitor, and has been found to
ameliorate vascular contraction and platelet aggregation. Suzuki et al 2008
analyzed the surveillance data of 3690 patients comparing the safety and
efficacy of fasudil plus ozagrel to fasudil alone. The occurrence of low density
areas on CT and symptomatic vasospasm were significantly lower in the
fasudil alone group. There was no difference with regard to adverse effetcs.
Hence, the combination of fasudil plus ozagrel was well tolerated, but did not
result in better efficacy than fasudil alone 55.
The experimental use of controlled-release biocompatible compounds
that deliver a desired drug locally into the subarachnoid space is under
investigation. This technology makes it possible to achieve high local
concentrations of therapeutic agents while minimizing systemic toxicity and
circumventing the need to cross the blood-brain barrier. Animal studies have
shown promising results, and the few human studies that have been
published using controlled-release systems with papaverine or nicardipine
report similarly encouraging outcomes 56.
Magnesium Sulfate
Wong et al, 2006, compared in 60 patients with aneurysmal SAH the
effect of magnesium
sulfate (MgSO4) 80 mmol/day plus Nimodipine with
Nimodipine alone. There was a strong trend to decrease the incidence of
21
symptomatic vasospasm from 43% to 23% by MgSO4 infusion. Duration of
elevated mean flow velocity > 120 cm/s was significantly decreased by
MgSO4 (p<0.01). However, there was no significant effect on functional
recovery or Glasgow Outcome Score. The incidence of adverse events such
as brain swelling, hydrocephalus, and nosocomial infection was comparable
57.
A study recruiting approximately 800 patients would be required to test for
possible neuroprotective effects of MgSO4 after SAH.
Statins
Independent of their cholesterol-lowering effect, statins have multiple
biological properties, including downregulating inflammation and upregulating
endothelial NO synthase. Thus, a positive effect on vasospasm may be
hypothetized. In a single center pilot study, Lynch JR et al randomized 39
patients with angiographically documented aneurysmal SAH to receive either
simvastatin (80 mg daily) or placebo for 14 days. Highest mean MCA TCD
velocities were significantly lower in the simvastatin-treated than in the
placebo group (p<0.01)
58.
These findings were confirmed by Kerz T et al
2008, enrolling 100 patients into a case control study 59.
Cortisone
Hyponatremia following SAH is a result of excess renal sodium
excretion (natriuresis), and may occur in 10 to 34% of those patients
Sodium
replacement
may
induce
further
sodium
excretion.
60.
The
mineralocorticoid properties of either fludrocortisones or hydrocortisone (1200
22
mg/day) promote renal sodium retention and attenuate hyponatremia and
hypovolemia in patients with SAH 61.
Tirilazad
Oxygen radical-induced, iron-catalyzed lipid peroxidation within the
vascular wall may play a key role in the occurrence of vasospasm. The 21aminosteroid tirilazad mesylate was developed (Pharmacia & Upjohn) as a
potent inhibitor of lipid peroxidation and may work by a combination of radical
scavenging and membrane stabilizing properties. Indeed, in experimental
models of SAH and focal cerebral ischemia tirilazad has been shown to
ameliorate vasospasm and improve cerebral blood flow as well as reduce the
size of cerebral infarction
62,63.
Recently, a meta-analysis of 5 randomized
clinical trials of tirilazad including 3,797 patients with SAH was published
64.
Tirilazad did not significantly decrease unfavorable clinical outcome on the
GOS (odds ratio [OR] 1.04, 95% confidence interval [CI] 0.89-1.20) or
cerebral infarction (OR 1.04, 95% CI 0.89-1.22). However, there was a
significant reduction in symptomatic vasospasm in patients treated with
tirilazad (OR 0.80, 95% CI 0.69-0.93) 64.
Ebselen
Ebselen is a seleno-organic compound with antioxidant activity that may act
through a glutathione peroxidase–like action. In a multicenter, placebocontrolled, double–blind clinical trial enrolling 286 patients with SAH oral
ebselen treatment (150 mg, twice a day) was compared with placebo. The
incidence of clinically diagnosed delayed ischemic neurological deficits was
23
unaltered. There was a significantly better outcome after Ebselen treatment
(p=0.005, chi2 test), and a decrease in the incidence and extent of lowdensity CT-areas (p=0.032, Wilcoxon rank sum test) 65.
Panax notoginseng saponins
Panax notoginseng (Burk) F.H. CHEN is a herb whose roots are used
in Chinese medicine and its extracts and major compounds, such as
ginsenosides and the notoginsenoside exert various pharmacologic activities.
Triterpenoid saponins are the major bioactive constituents, and the underlying
mechanism of its action is anti-inflammatory and may contribute to
neuroprotective effects in brain ischemia 66.
SURGICAL TREATMENT
Ventricular CSF Drainage
From a mechanical point of view, removal of cerebrospinal fluid (CSF)
containing clot following SAH would reduce the amount of hemoglobin
breakdown products and may prevent or reverse cerebral vasospasm (Figure
8). In a series of Sonobe et al, 185 patients operated on for aneurysmal SAH,
the incidence of vasospasm was 11% in 150 patients with CSF drainage and
29% in 35 patients without drainage
67.
In a series of Ito et al, 25 SAH patients
underwent clipping and cisternal CSF drainage. The effect of the drainage
was graded as fair (>150 mL/day), moderate (50-150 mL/day), or poor (<50
mL/day). Symptomatic vasospasm occurred in 32, 60, and 78 % of patients
with fair, moderate, and poor drainage, respectively
68.
Contrarily, in a series
of Kasuya et al, in 92 patients operated on for aneurysmal SAH the incidence
24
of cerebral infarction at 48 hours was higher in patients with higher CSF
drainage volumes 69.
Figure 8: Surgical view of a ventricular CSF drainage. During the craniotomy
a frontal hole may be done in order to access the ventricle with a catheter and
begin draining CSF. After the clipping a ventricular catheter may be kept in
the post operatory period.
Lumbar CSF drainage
Alternatively to a ventricular drainage, lumbar drainage may clear blood
from the basal cisterns. Lumbar drainage may be safer and more easily
performed than a ventricular drainage. In a retrospective study, Schmidt and
Klimo observed less cerebral vasospasm following lumbar drainage than
without lumbar drain (p<0.001), with a better recovery in the group treated
with lumbar drainage 70.
Thrombolytic therapy
Intracisternal thrombolytic therapies may aid in clearing blood from the
CSF. Recombinant TPA has been used in several clinical trials with moderate
success. Findlay et al reported to decrease the rate of vasospasm by a single
dose of rTPA instilled at the time of surgery 71. In a cohort study, Kodama et al
treated 217 patients with a combination of ventricular drainage and
continuous intrathecal irrigation with urokinase and ascorbic acid 72.
Fenestration of the lamina terminalis
In more than 60% of SAH patients, a coexistence of vasospasm and
hydrocephalus is observed 73,74. Anecdotal reports suggest that fenestration of
25
the lamina terminalis during surgery could improve the outcome and might
decrease the rate ventriculoperitoneal shunting for hydrocephalus
75,76,77.
Fenestration of the lamina terminalis (Figure 9) can be performed with
or without additional fenestration of the membrane of Liliequist (Figure 10)
78,79.
In a series of 100 patients, Fisher grade 3, Andaluz and Zucarello
reported a reduction of vasospasm from 53% in patients without lamina
terminalis fenestration to 33% with fenestration (p<0.001)
80.
Figure 9: Surgical view after anterior communicating artery aneurysm
clipping, the fenestration of lamina terminalis between the two optic nerves is
perfomed by us as routine.
Figure 10: Microsurgical fenestration of Liliequist membrane and remove
clots from interpeduncular cistern is extremely useful against the develop of
vasospasm.
ENDOVASCULAR TREATMENT
Endovascular
treatment
options
include
angioplasty and intraarterial papaverine infusion
81,
transluminal
balloon
and may be applied for
treatment of vasospasm in those patients who have failed conventional
therapy
44.
Several uncontrolled studies indicate that transluminal angioplasty
may provide neurologic improvement. Hemodynamic effects resulting from
angioplasty of vasospastic arteries can be quantified using combined
perfusion- and diffusion-weighted (PW/DW) magnetic resonance (MR)
26
imaging. In cases of a severe PW/DW mismatch, successful angioplasty of
proximal vasospasm improved tissue perfusion and prevented cerebral
infarction 82.
GENE THERAPY
Transfer of genes that encode vasoactive products via the CSF may prevent
vasospasm after SAH. Alternatively, neuroprotective genes, or genes
targeting proinflammatory mediators may reduce ischemic stroke. Several
fundamental advances, as improvement of vectors, are required before gene
therapy can be adopted in clinical routine 83.
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