Detecting and treating microvascular ischemia after
subarachnoid hemorrhage
Oliver W. Sakowitz and Andreas W. Unterberg
Purpose of review
To provide an overview of the current management of
cerebral vasospasm following subarachnoid hemorrhage,
emphasizing the detection and treatment of delayed
ischemia.
Recent findings
Sensitive and specific monitoring methods are necessary to
register the onset of cerebral vasospasm early to prevent
long-term morbidity and mortality. Therefore, various
techniques to measure cerebral perfusion and/or surrogate
parameters have been developed. Prophylaxis with calcium
antagonists such as nimodipine is administered for
neuroprotection. Resolution of ongoing cerebral
vasospasm can be achieved by either dilating constricted
vessels or optimizing hemodynamics. Therapeutic
treatment with hypertension, hypervolemia and
hemodilution (HHH) has a direct influence on cerebral
vasospasm, ischemic sequelae and outcome, while
prophylactic HHH leads to excess complications. Other
treatments, for example endothelin antagonists, statins or
magnesium salts, used to prevent or treat cerebral
vasospasm, are being tested. Endovascular treatment
options can be used for therapy-refractory cerebral
vasospasm, but they carry procedure-related risks and may
be short-acting.
Summary
Diagnosis of microvascular ischemia following
subarachnoid hemorrhage involves clinical observation,
non-invasive determination of cerebral hemodynamic
variables, autoregulation studies and invasive online
monitoring of cerebral oxygenation and metabolism.
Nimodipine is administered prophylactically, while HHH is
initiated therapeutically. New causal therapies are being
evaluated.
Keywords
aneurysmal subarachnoid hemorrhage, cerebral
monitoring, delayed ischemia, stroke, vasospasm
Curr Opin Crit Care 12:103–111. ß 2006 Lippincott Williams & Wilkins.
Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany
Correspondence to Prof. Dr. med. Andreas W. Unterberg, Department of
Neurosurgery, University of Heidelberg, Im Neuenheimer Feld 400, D-69120
Heidelberg, Germany
Tel: +49 6221 56 6300; fax: +49 6221 56 5534;
e-mail: andreas.unterberg@med.uni-heidelberg.de
Current Opinion in Critical Care 2006, 12:103–111
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Abbreviations
CBF cerebral blood flow
DIND delayed ischemic neurological deficit
HHH hypertension, hypervolemia, hemodilution
SAH subarachnoid hemorrhage
sjvO2 jugular-venous saturation of oxygen
TCD transcranial Doppler sonography
VSP cerebral vasospasm
ß 2006 Lippincott Williams & Wilkins
1070-5295
Introduction
Stroke from all causes is the third-most frequent killer
worldwide. About 5% of these deaths are related to
aneurysmal subarachnoid hemorrhage (SAH). In contrast
to acute ischemic stroke, secondary ischemia from SAH is
seen in a remarkable percentage of patients, who are
already hospitalized at the peak time of occurrence.
Therefore, the detection and treatment of ischemia
following SAH as well as understanding its underlying
causes and pathophysiological cascades are an outstand-
ing challenge for the involved clinician, clinical resear-
cher and basic scientist.
Definitions
The first description of cerebral vasospasm (VSP) follow-
ing SAH was based on the angiographical findings of
reduced vessel calibers in the basal cerebral arteries [1]. It
usually occurs within 4–10 days of SAH (Fig. 1a). About
two-thirds of all patients develop angiographic signs of
vasospasm (angiographic VSP), and about half of these
decompensate and develop clinical symptomatology
including fluctuations in the level of consciousness,
motor weakness, aphasia or other (symptomatic or clinical
VSP) [2,3]. Two types of VSP have been identified:
proximal (i.e. mainly affecting extraparenchymal vascula-
ture) and distal (i.e. mainly affecting intraparenchymal
vasculature).
In clinical practice two time frames for ischemic events
have been observed in SAH patients. Accordingly, acute
ischemic neurological deficits as a consequence of, for
example, primary intraparenchymal hemorrhage, intra-
cranial hypertension, hypoxia and arterial hypotension,
have to be discerned from delayed ischemic neurological
deficits (DINDs). The latter are mostly the manifes-
tations of VSP and are thus widely used synonymously
with symptomatic VSP.
103
 104 Neuroscience
Figure 1 Pathophysiology of cerebral vasospasm
(a) Timing and incidence of aneurysmal rerupture and cerebral vasos-
pasm. (b) Disturbed pressure autoregulation following subarachnoid
hemorrhage. (c) Dysequilibrium of vasodilation and vasoconstriction,
with mediators suspected in the pathogenesis of cerebral vasospasm.
CBF, cerebral blood flow; CPP, cerebral perfusion pressure; nl, normal;
SAH, subarachnoid hemorrhage; VSP, cerebral vasospasm.
Pathophysiology
Pathophysiologically, cerebral ischemia is defined by a
cerebral blood flow (CBF) that is insufficient to meet the
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
metabolic demands of the brain tissue leading to cellular
energy failure, breakdown of ion homeostasis, calcium
overload, mitochondrial dysfunction, and ultimately the
demise of the affected brain territory.
The cerebral perfusion pressure is defined as the differ-
ence between mean arterial pressure and intracranial
pressure. Physiologically, CBF is maintained constant
over a wide range (50–150 mmHg) of cerebral perfusion
pressure (Fig. 1b). This is mainly due to pressure auto-
regulation of the cerebrovascular resistance.
Consequently, the autoregulation curve in victims of
SAH, who are regularly at risk for VSP and increa-
sed cerebrovascular resistance, is shifted to the right
(Fig. 1b).
Cerebral vasospasm — disturbed equilibrium
of dilation and constriction?
In the past 20 years our knowledge of VSP has increased
remarkably [4

]. Although the pathophysiology of VSP
is ultimately unclear, the occurrence of a localized blood
clot in a perivascular distribution seems to be a triggering
factor [5]. It is hypothesized that spasmogenic factors
released from the clot disturb the equilibrium of vaso-
dilatory and vasoconstricting mediators (Fig. 1c). Both
calcium-dependent and calcium-independent pathways,
triggered through G-protein-coupled receptors and
receptor tyrosine kinases, have been suggested.
In addition to the well-described macroscopic vasosp-
asm of the basal cerebral vasculature, microcirculatory
changes have gained substantial interest in recent years.
Today, various pathophysiological cascades from protein
kinase activation, NO scavenging by (de)oxyhemoglo-
bin, increased endothelin activity and changes in con-
tractile receptor subtypes to altered intracellular calcium
signaling and/or accompanying structural changes of
the vasospastic arterial wall (e.g. inflammation, proli-
feration, apoptosis) have been revealed (for review
see [6]).
While experimental investigations on the pathogenesis of
VSP and potential therapeutic targets are underway,
pragmatic approaches have been taken in the clinical
field, where early detection of secondary ischemia from
VSP is essential to prevent or ameliorate progressing
brain injury. The following review highlights important
clinical features related to the diagnosis and treatment of
VSP and the resulting DIND.
Diagnosis of delayed ischemia following
subarachnoid hemorrhage
In the clinical setting VSP and resulting DIND can be
detected on the basis of cerebral tissue function, per-
fusion, oxygenation and/or metabolism.
 Ischemia after subarachnoid hemorrhage Sakowitz and Unterberg 105

Cerebral tissue function
Functional integrity of cerebral tissues can be assessed
clinically or by neurophysiologic monitoring.
Clinical evaluation
Long before its identification by modern imaging tech-
niques, VSP and the resulting DIND were anecdotally
described. The first comprehensive investigation of
neurological worsening following SAH was published
by Fisher in 1975 [7]. In this series DIND occurred
between days 3 and 13 following SAH and took 2–4 days
to reach their maximum. Angiographic VSP was demon-
strated in 40% of all patients, who became symptomatic
only when vessel narrowing was severe. About one-third
of survivors developed symptoms of DIND in terms of
paresis, dysphasia, agnosia, apraxia, frontal lobe signs or a
reduced level of consciousness. One-half of these symp-
toms were reversible over the course of several months.
The lessons from this study have not changed: severe
VSP results in neurological symptoms that can be detected
by clinical evaluation and may be partially reversible.
Therefore, early detection and aggressive treatment of
new-onset ischemic symptoms is crucial and there is an
ongoing mandate for bedside methods to objectify DIND.
Currently available diagnostic methods for the detection
of symptomatic vasospasm will be reviewed in the fol-
lowing sections. Wherever possible, sensitivity and
specificity of the respective modality with regard to
symptomatic VSP have been emphasized. A compre-
hensive summary is given in Table 1.
Continuous neurophysiologic monitoring
Recordings of the superficial electroencephalogram
reflect the sum of excitatory and inhibitory postsynaptic
potentials in the adjacent cortex. At a CBF below 20 ml/
100 g per min the electroencephalogram activity is
reduced and it eventually ceases at a terminal depolariza-
tion threshold of 10 ml/100 g per min. Spectral analyses
and derived indices (e.g. a/d ratio, relative a variability)
may facilitate early detection of secondary ischemia [8].
According to the few studies available, sensitivity and
specificity for the detection of VSP is high [9
]. Con-
tinuous electroencephalogram assessment is technically
feasible, but not widely used. It requires stable recordings
with low signal-to-noise ratios and specially trained tech-
nical staff, which hampers its use in the setting of the
intensive care unit.
Cerebral tissue perfusion
VSP impairs tissue perfusion if collateral flow is insuffi-
cient. Several methods have been proposed to detect
perfusion deficits, before manifest neurological deteriora-
tion occurs.
Transcranial Doppler ultrasonography
By means of transcranial Doppler sonography (TCD),
flow velocities can be measured in the proximal cerebral
vasculature. Assuming a relatively stable CBF it is there-
fore possible to gather information about proximal
cerebral vessel diameters.
The value of TCD has been both overestimated and
overcriticized in the past. In principle it is a non-invasive
measurement for bedside usage [10]; however, it is lim-
ited in VSP detection. The measurement has a high inter-
observer variability [11]. Owing to the fact that blood-
flow velocity depends on more than one factor (e.g. vessel
diameter, insonation angle, cerebral blood volume flow)
the specificity of the method is low [12,13]. Increases
in flow velocity can stem from VSP with consecutive

Table 1 Detection of microvascular ischemia by numerous methods given in hierarchical sequence (function, perfusion, oxygenation,
metabolism)

Monitoring Invasiveness Risks Sensitivity Specificity References

Function
Clinical evaluation 0 None NA NA
Electroencephalogram 0 None 89–100% 76–84% [9
]
Perfusion
Intracranial pressure/CPP þ Hemorrhage, infection NR NR
Angiography þ Radiation, transport, hemorrhage, embolism 75–100% 53–63% [13,17,75]
TCD 0 None 59–88% 50–100% [12,13,16–20]
Xe-CT, SPECT, PET, etc. 0 Radiation, transport Var Var [23,26,27]
Tissue perfusion þ Hemorrhage, infection 90% 75% [16]
Oxygenation
Jugular bulb oximetry þ Complications of access route, infection, thrombosis 90–100% 55–64% [34
]
Tissue oxygenation þ Hemorrhage, infection NR NR [37]
Metabolism
CSF chemistry þ Hemorrhage, infection NR NR [38]
Microdialysis þ Hemorrhage, infection 82–94% 88–89% [13,43

]
Invasiveness: 0, non-invasive; þ, invasive. Sensitivity and specificity to detect symptomatic cerebral vasospasm are as reported in the given references.

Symptomatic cerebral vasospasm or cerebral vasospasm leading to permanent ischemia. CPP, cerebral perfusion pressure; CSF, cerebrospinal fluid;
NA, not applicable; NR, not reported; PET, positron emission tomography; SPECT, single-photon emission tomography; TCD, transcranial Doppler
sonography; Var, varies by method; Xe-CT, xenon-enhanced computed tomography.

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 106 Neuroscience
hypoperfusion as well as from hyperemia, following
enhanced hemodynamics [14,15]. Accordingly, a wide
range of sensitivities and specificities has been deter-
mined by several authors [12,13,16–20]. Additional stu-
dies (e.g. cerebral perfusion imaging) are necessary to
validate deviant TCD measurements.
Other applications, such as cerebrovascular reactivity
studies to measure cerebral autoregulation, are not com-
monly used in clinical diagnostics of SAH patients.
Besides the inherent risks of these studies, the funda-
mental critique is based on the significant differences
between TCD flow velocity measurements and measure-
ments of CBF [21]. Technical shortcomings and inac-
curacies owing to angle-dependency and time-dependent
variations in velocity profiles and vessel diameters could
potentially be solved by new-generation digital Doppler
ultrasound and dual-beam technology.
Cerebral perfusion imaging
Ideally, monitoring for VSP would encompass continu-
ous (bedside), multi-regional perfusion measurements.
Currently only one or the other is technically feasible.
Xenon-enhanced computed tomography has been used
since the late 1970s and is considered the gold-standard
method, where stable xenon is inhaled and circulates to
the target organ [22]. Both positron emission tomogra-
phy and single-photon emission tomography are based
on localized emission of gamma particles from the
decay of inhaled or injected radionuclides. They can
be used to obtain ‘snapshots’ of brain perfusion and
metabolism.
All of these methods have been used to demonstrate
delayed perfusion deficits due to VSP [15,23–27].
Relatively demanding on clinical resources, they are
usually complementary and coupled to continuous
bedside monitoring techniques to verify uncertain
results that may represent VSP. Thus, sensitivity and
specificity vary largely with the respective method. A
full discussion of benefits and drawbacks of each indi-
vidual technique, however, is beyond the scope of this
review.
Recently, new algorithms and fast scanning techniques
have been developed to extrapolate CBF by means of
perfusion-weighted imaging. Both computed tomogra-
phy and magnetic resonance imaging can be coupled
with triggered contrast-boli and used to calculate CBF,
cerebral blood volume and mean transit time in patients
with SAH [28,29]. The utility is still under investigation,
but considerable efforts are being taken to minimize
contrast burden and imaging time. In the near future
perfusion imaging studies could be integrated into rou-
tine protocols for SAH patients undergoing repeated
imaging for various reasons.
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Cerebral tissue perfusion monitoring
VSP most likely affects those parts of the cerebral
vasculature in contact with SAH, and higher amounts
of clot increase the risk for DIND [5]. Therefore, regions
of tissue at risk can be determined where local monitor-
ing techniques can be applied. A number of new
devices are currently being investigated, which allow
for continuous monitoring of local CBF by laser-Doppler
flowmetry [30] or thermal dilution techniques [16,31].
The safety of these intraparenchymal microsensors has
been reported as good. Especially in comatose patients,
for whom intracranial pressure monitoring is mandatory
anyway, this procedure can be done without increasing
invasiveness.
Cerebral tissue oxygenation
Physiologically, cerebral perfusion is coupled to the
demands for adequate tissue supply with oxygen and
nutrients.
Jugular-bulb oximetry
Continuous monitoring of oxygenation parameters is
thought to supplement or even substitute CBF measure-
ments. If the cerebral metabolic rate of oxygen consump-
tion is constant, CBF is inversely proportional to the
arteriovenous difference in oxygenation. Given that
jugular-venous saturation of oxygen (sjvO2) can be
continuously monitored after retrograde insertion of a
fiberoptic catheter into the jugular-venous bulb, arterio-
venous difference in oxygenation can be calculated.
Clinically, in patients with stable arterial oxygenation,
sjvO2 is used directly to guide therapy.
In SAH patients this method has been applied with good
success when monitoring for sjvO2 desaturations during
severe VSP [32] or when following its improvement
during interventional perfusion augmentation [33]. Pro-
blems arise from technical artifacts due to neck move-
ments, misplaced catheters or anatomical variants. From
the earlier theoretical considerations it becomes clear
that sjvO2 is a monitor of global oxygenation, whereas
malperfusion of small vascular territories might be
missed. Lactate measurements and respective indices
might improve diagnostic sensitivity and specificity [34
].
Tissue oxygenation
A localized pendant to ‘global’ sjvO2 measurements has
therefore been developed in miniature parenchymal
sensors based on a Clark-type electrode or phosphor-
escence quenching phenomena transmitted via glass
fibers. The latter technique can be employed with co-
sensors for tissue pH and CO2 tensions, which are less
explored targets in the monitoring of SAH patients at
present [35]. It has been shown that episodes of tissue
hypoxia are quite frequent in SAH patients and that they
are associated with a less favorable outcome [36]. This
 Ischemia after subarachnoid hemorrhage Sakowitz and Unterberg 107
view is challenged, however, by another study in which
tissue oxygenation was compared in survivors and non-
survivors of SAH and no difference could be found
except on the final day of monitoring [37]. Thus, one
can conclude that tissue oxygenation monitoring may
allow one to follow individual trends and to react thera-
peutically to counter local tissue ischemia, but must not
be mistaken for a ‘crystal ball’ that can predict the
ultimate outcome.
Cerebral tissue metabolism
In analogy to diagnostics of other organ systems, it would
be favorable to have sensitive and specific biochemical
markers to detect delayed cerebral ischemia early in
its beginning.
Cerebrospinal fluid chemistry
It has been suggested that cerebrospinal fluid chemistry
may be viewed as a global measurement of cerebral
metabolism. Cerebrospinal fluid is easily obtained in
most SAH patients since diversion by external ventricular
drainage systems is performed in the majority of cases
anyway. Ventricular cerebrospinal fluid lactate has been
suggested as a significant parameter to monitor for VSP
[38], but the slow rate of cerebrospinal fluid turnover
limits this application. So far no early indicators of ische-
mia have been identified that might be used routinely to
monitor SAH patients.
Cerebral microdialysis
Cerebral ischemia ultimately leads to the breakdown of
the combined neuronal and glial energy metabolism. It
has therefore been hypothesized that monitoring of
cerebral metabolism could be used to identify significant
ischemia sensitively enough to act in due time, yet
specific enough to prevent overtreatment.
Bedside or online microdialysis was introduced in neu-
rocritical care in the late 1990s and is used to measure
changes in tissue concentrations of low-molecular-weight
compounds such as glucose, lactate, pyruvate, glutamate,
and glycerol [39–41]. Details of the method are given in a
dedicated article by Hillered et al. [42].
Clinical studies comparing this technique with TCD
have identified a similar sensitivity, but higher specificity
in the detection of secondary ischemia in SAH patients
with angiographical and symptomatic VSP [13,43

]. The
order of metabolic changes thereby preceded clinical
deterioriation in 83% of cases, leaving the opportunity
to initiate therapeutic measures earlier than the anticip-
ated neurological worsening [44].
The clinical grades of SAH patients are reflected by
deranged metabolic parameters such as increased tissue
lactate and lactate/pyruvate ratios. Similarly, clinical
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outcomes were significantly worse, independent of
clinical grading or patient age [36,45
].
The technical drawbacks of microdialysis are mostly
related to the restriction to a small volume of tissue
parenchyma. Careful choosing of the location is necessary
to yield the low false-negative rates of 10–15% that are
observed [13]. Initial investment costs and maintenance
intensity are considerably higher than for TCD.
Microdialysis may become a monitoring method of
choice in high-grade SAH. For a more complete review
on microdialysis in neurocritical care the reader is
referred to [46

].
Treatment of delayed ischemia following
subarachnoid hemorrhage
Treatment of VSP and resulting DIND starts on admis-
sion to the neurocritical care unit. Several surgical and
medical options are currently used for prophylaxis, risk
reduction and treatment of microvascular ischemia.
Where these fail, options for interventional perfusion
augmentation have been proposed (see Table 2).
Surgical options
Back in the 1970s, the principle treatment of aneurysmal
SAH was first to stablize the clot (e.g. with antifibrinoly-
tic drugs, antihypertensive drugs, etc.) to reduce the
rate of acute rebleeding, and then to proceed with surgi-
cal aneurysm obliteration (e.g. microsurgical clipping)
in a delayed fashion. This may have resulted in increases
in frequency and severity of VSP. With the advent of
early microsurgical clipping (i.e. within 72 hours follow-
ing hemorrhage) it became feasible to eliminate blood
from basal cisterns following aneurysm obliteration [47,
48]. Today, intraoperative adjuvant and postoperatively
continuing cisternal thrombolysis with fibrinolytic agents
such as recombinant tissue plasminogen activator or uro-
kinase are debated, but the only randomized-controlled
Table 2 Standard, optional and experimental treatment
measures for delayed ischemic neurological deficit following
subarachnoid hemorrhage
Treatment measure
Standard
Nimodipine (oral)
Hyperdynamic treatment (‘triple-H’)
Optional
Transluminal balloon angioplasty
Super-selective intravascular vasodilator treatment
Experimental
NO donors
Statins
Magnesium salts
Endothelin antagonists
Rho kinase inhibitors
 108 Neuroscience
trial to date yielded negative results [48]. In contrast,
treatment of posthemorrhagic hydrocephalus and clear-
ance of intraventricular hemorrhage by external ventri-
cular drainage have proven efficacious empirically and are
performed by the majority of neurosurgeons.
New treatment options involving intraoperative place-
ment of biodegradable controlled-release pharmaceutical
carriers (e.g. absorbable polymers, pellets) are currently
being developed [49
,50]. The benefits of continuous
local release over systemic treatment are obvious, but
larger clinical trials are definitely needed to clarify
efficacy and to assess safety.
Medical options
Several pharmacological agents for the treatment of
cerebral VSP and its sequelae have been developed in
the past three decades.
Calcium-channel blockers
Prophylactic treatment with calcium antagonists such as
nimodipine was implemented in the early 1980s [51–53],
and these are still the only substance proven to be
beneficial following SAH. An oral dosing regimen is
recommended over intravenous application, which is
currently not approved by the US Food and Drug Admin-
istration, but available outside of the USA. The latter
mode has never been proved to be efficacious, since its
neuroprotective capabilities are possibly offset by more
frequently occuring side effects (i.e. arterial hypoten-
sion). Conflicting data exist for oral nimodipine regarding
the (dis)advantages in patients in poor clinical condition
on admission or in patients with established cerebral
ischemia [54

].
Mechanisms of calcium sensitization are discussed
regarding VSP following SAH. The Rho kinase pathway
is G-protein-coupled, activated following SAH and
results in smooth muscle contraction. Fasudil (AT877),
a Rho kinase inhibitor currently available on the Japanese
market, has been found to reduce the relative risk of
developing angiographic VSP and secondary ischemia,
but data on patient outcome are inconclusive so far
[54

,55].
Steroids
The use of corticosteroids in SAH has been controversial.
Glucocorticosteroids, such as dexamethasone, are prescri-
bed with the intent to reduce brain edema and neuroin-
flammation. Mineralocorticosteroids, like fludricortisone,
are administered to counter hyponatremia and fluid loss.
A recent meta-analysis has revealed a clear lack of scien-
tific evidence, both for the use of corticosteroids in
improving clinical outcomes or in preventing the
development of cerebral ischemia, as well as a plethora
of significant adverse effects [56

].
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Aminosteroids, such as tirilazad, are potent inhibitors
of lipid peroxidation, but lack glucocorticoid proper-
ties. Two randomized, double-blind, vehicle-controlled
multicenter studies were completed to study efficacy
in SAH patients of all grades. A significant reduction of
mortality from all causes was first demonstrated in
male patients but could not be reproduced later on
[57,58]. Additional studies with a higher dosage in
women failed to improve mortality and outcome but
nominally reduced incidence of clinical vasospasm
[2,3]. According to subgroup analyses, poor-grade
SAH patients of both sexes might benefit from
tirilazad treatment, but this effect was not statistically
robust.
Overall, the evidence base for steroid treatment in SAH
patients is weak and none of the tested substances can be
recommended at present.
Others
Recently experimental studies of VSP reversed by
local or systemic replacement of vasodilatory NO have
triggered substantial interest [50,59] and have led to
compassionate use applications, for example where
sodium nitroprusside, a strong NO donor, was infused
intrathecally to treat and prevent therapy-refractory VSP
[60].
Endothelins and their respective receptors have been
identified and described as potential pathogens in the
development of VSP. Recently, promising results with a
reduction in the occurrence and severity of angiographic
VSP have been attained with clazosentan, a novel
endothelin receptor antagonist [61
].
Magnesium inhibits the release of excitatory amino acids,
blocks N-methyl-D-aspartate receptors, and has a dilata-
tory effect on cerebral arteries. In a recent multicenter
study, continuous infusions of magnesium sulfate for up
to 14 days after aneurysm occlusion resulted in a
reduction of DIND and improvement in outcome after
3 months in SAH patients of all grades. The study was
underpowered, however, for a definite conclusion and a
larger study with the aim of enrolling approximately 1100
patients is planned [62
].
Statins were originally introduced as inhibitors of the
hepatic 3-hydroxy-3-ethylglutaryl coenzyme A reduc-
tase involved in cholestorol metabolism. Furthermore,
acute statin therapy has been suggested to augment CBF
through NO-related mechanisms and ameliorate
proliferative vasculopathy. In a trial of oral pravastatin
for up to 14 days following hemorrhage a significant
reduction in the occurrence and severity of VSP was
demonstrated. Definite outcome data are pending
[63
].
 Ischemia after subarachnoid hemorrhage Sakowitz and Unterberg 109
Hyperdynamic therapy
Given the changes in pressure autoregulation seen with
VSP, the intuitive reaction is to augment systemic blood
pressure (‘hypertension’) and thereby achieve adequate
perfusion on the sigmoid perfusion curve. Similarly,
according to Poiseuille’s law, hemorheologic impro-
vement is sought in intravascular fluid expansion (‘hy-
pervolemia’) with crystalloid and colloid infusions
(‘hemodilution’). The combination of these treatments
has become standard in the neurosurgical intensive
care unit under the acronym ‘triple-H’ therapy. Contro-
versy exists whether hypertension, hypervolemia,
hemodilution (HHH) therapy should be used prophy-
lactically or therapeutically; that is, only when VSP
occurred. In the 1990s prophylactic hyperdynamic treat-
ment of VSP was widely used [2,64]. Side effects, like
cardiac failure, electrolyte abnormalities, cerebral edema
and bleeding abnormalities are well known. Moreover,
while therapeutic HHH therapy – though never sub-
mitted to formal trial – has a direct influence on vasos-
pasm, ischemic sequelae and outcome, prophylactic
HHH therapy is lacking evidence of these beneficial
effects [2,65–68]. Moreover, surrogate parameters of
tissue oxygenation and microdialysis glutamate, respect-
ively, indicate a favorable effect of therapeutic HHH
[43,69
].
Interventional perfusion augmentation
Increased use of endovascular treatment options for
cerebral aneurysm occlusion has been accompanied by
new developments to treat VSP by intervention as well.
Intravascular vasodilator treatment
Vasodilating pharmaceuticals can be administered during
endovascular procedures, but there have been no rando-
mized and controlled studies to show effects superior to
medical treatment. One benefit is that high substance
concentrations can be achieved in a spastic vessel terri-
tory without overly affecting systemic arterial pressure.
Thus, even distal VSP can be treated. A major drawback
is that the effect of treatment with several agents
(e.g. papaverine, nimodipine, fasudil) is relatively
short-lived and repeated endovascular treatment sessions
are necessary to maintain an effect [70,71].
Transluminal balloon angioplasty
Transluminal balloon angioplasty has been positively
described in a number of uncontrolled case series and
retrospective analyses [72]. Other authors have even
suggested prophylactic balloon angioplasty to lower the
incidence of VSP and a multi-center, randomized con-
trolled clinical trial is still ongoing [73]. Only proximal
VSP is amenable to this treatment. The most recent out-
come studies question the efficacy of adjunct angioplasty
over medical management [74]. Additionally, high com-
plication rates of approximately 5% (e.g. vessel rupture,
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
catheter embolism, clip dislocation) may indicate that
angioplasty is less safe than medical treatment and should
therefore be reserved for therapy-refractory VSP.
Conclusion
Diagnosis of microvascular ischemia following SAH has
evolved from clinical observation to non-invasive deter-
mination of cerebral hemodynamic variables, autoregula-
tion studies and invasive online monitoring of cerebral
oxygenation and metabolism. Especially the latter
methods are fit for the timely diagnosis of ischemia with
a high sensitivity and specificity. Standard treatment is
prophylaxis with oral administration of nimodipine and
improvement of cerebral perfusion pressure with HHH
therapy. New causal therapies (e.g. endothelin antago-
nists, statins, magnesium salts) are currently being
evaluated.
Acknowledgements
We thank Mrs Kara Leigh Krajewski for reviewing the manuscript and
editing the language. All artwork was produced by Mrs Dorothea
Mews-Zeides.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:

of special interest


of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (pp. 179–180).
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