Neurocrit Care

https://doi.org/10.1007/s12028-023-01747-9

PRACTICE GUIDANCE FOR THE NEUROCRITICAL CARE MANAGEMENT OF SAH

Therapies for Delayed Cerebral Ischemia

in Aneurysmal Subarachnoid Hemorrhage
Vishank A. Shah1*  , L. Fernando Gonzalez2 and Jose I. Suarez1

© 2023 Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society

Abstract 
Delayed cerebral ischemia (DCI) is one of the most important complications of subarachnoid hemorrhage. Despite
lack of prospective evidence, medical rescue interventions for DCI include hemodynamic augmentation using
vasopressors or inotropes, with limited guidance on specific blood pressure and hemodynamic parameters. For DCI
refractory to medical interventions, endovascular rescue therapies (ERTs), including intraarterial (IA) vasodilators and
percutaneous transluminal balloon angioplasty, are the cornerstone of management. Although there are no rand-
omized controlled trials assessing the efficacy of ERTs for DCI and their impact on subarachnoid hemorrhage out-
comes, survey studies suggest that they are widely used in clinical practice with significant variability worldwide. IA
vasodilators are first line ERTs, with better safety profiles and access to distal vasculature. The most commonly used IA
vasodilators include calcium channel blockers, with milrinone gaining popularity in more recent publications. Balloon
angioplasty achieves better vasodilation compared with IA vasodilators but is associated with higher risk of life-
threatening vascular complications and is reserved for proximal severe refractory vasospasm. The existing literature
on DCI rescue therapies is limited by small sample sizes, significant variability in patient populations, lack of standard-
ized methodology, variable definitions of DCI, poorly reported outcomes, lack of long-term functional, cognitive, and
patient-centered outcomes, and lack of control groups. Therefore, our current ability to interpret clinical results and
make reliable recommendations regarding the use of rescue therapies is limited. This review summarizes existing
literature on rescue therapies for DCI, provides practical guidance, and identifies future research needs.
Keywords:  Anuerysmal subarachnoid hemorrhage, Delayed cerebral ischemia, Rescue therapies, Endovascular
rescue therapies, Intra-arterial vasodilators, Cerebral angioplasty

Introduction phenomenon has received variable nomenclature, often

More than 20% of the survivors of aneurysmal suba-
rachnoid hemorrhage (SAH) have long-term disability
and cognitive impairment [1–3]. Delayed neurological
deterioration in the acute phase, often a consequence of
focal or global cerebral ischemia [4], is the single most
“remediable” factor contributing to the prolonged mor-
bidity associated with SAH [3, 5, 6]. Traditionally, this
*Correspondence: vshah21@jhmi.edu
1
Division of Neurosciences Critical Care, Departments of Anesthesiology
and Critical Care Medicine, Neurology, and Neurosurgery, The Johns
Hopkins University School of Medicine, 1800 Orleans Street, Zayed 3014A,
Baltimore, MD, USA
Full list of author information is available at the end of the article
labeled as symptomatic vasospasm, delayed ischemic
neurological deficit [7] or delayed cerebral ischemia
(DCI) [4]. An international multidisciplinary consensus
committee, further endorsed by the National Institute
of Neurological Diseases and Stroke common data ele-
ments, agreed on DCI as the most appropriate termi-
nology for delayed neurological deterioration related
to cerebral ischemia after SAH [8]. Early detection and
timely treatment of DCI are an important component in
improving outcomes after SAH. Aggressive monitoring,
early treatment of DCI, and the advent of endovascular
rescue therapies (ERTs) have been associated with > 50%
reduction in SAH case fatality and morbidity over the
past decades [2, 4, 9]. This review article will discuss
available evidence, provide practice guidance, and iden-
tify future research needs in rescue therapies for DCI,
particularly ERTs.
Definitions
Delayed cerebral ischemia is a clinical phenomenon
defined as the appearance of focal neurological defi-
cits (motor limb weakness, aphasia, hemineglect, and/
or hemianopia) or a global neurological deficit (Glas-
gow coma scale decline by ≥ 2 points) related to ongoing
cerebral ischemia, lasting or fluctuating for a minimum
of 1  h, and/or appearance of new cerebral infarcts on
neuroimaging not explained by other clinical, radio-
logical, or laboratory abnormalities, and not occurring
immediately after aneurysm occlusion procedures [8,
10]. Contrarily, “angiographic vasospasm” is a radio-
logical phenomenon, defined as greater than two thirds
reduction in intracranial vessel diameter on neuroimag-
ing [7]. Based on degree of narrowing on angiographic
imaging, vasospasm is graded as grade I (0–25%), grade
II (26–50%), grade III (50–75%), and grade IV (> 75%).
“Sonographic vasospasm” is defined as mean blood flow
velocities ≥ 120  cm/s and Lindergaard ratio ≥ 3 [11] on
transcranial Doppler ultrasound (TCD). “Symptomatic
vasospasm” is defined as focal neurological deficits local-
izing to the vascular territories with vasospasm.
Pathophysiology of DCI
Historically, DCI was considered a direct consequence
of large-vessel vasospasm [4]. However, angiographic
vasospasm occurs in up to 70% of patients with SAH,
but only 30% develop clinical signs/symptoms and cer-
ebral infarcts [12–14]. While angiographic vasospasm
is not linked to poor outcomes, DCI is an independent
predictor of poor functional and cognitive outcomes [5,
6], making it an important therapeutic target [15]. Cla-
zosentan, an endothelin-receptor antagonist, was shown
to improve angiographic vasospasm but did not improve
clinical outcomes [7]. Conversely, nimodipine improves
functional outcomes, without substantially improving
angiographic vasospasm [16, 17]. Moreover, infarcts and
perfusion deficits related to DCI occur beyond vascular
territories with vasospasm [18, 19]. These findings indi-
cate that angiographic vasospasm is not entirely a reliable
indicator of DCI and suggest that other pathophysiologic
pathways may contribute to DCI [20, 21].
Leakage of arterial blood in to the subarachnoid space
after aneurysmal rupture triggers a transient acute eleva-
tion in intracranial pressure and consequent transient
global ischemia leading to early brain injury (EBI). EBI,
in conjunction with leaked endothelin-1 and oxyhemo-
globin, activate cell-death pathways, releasing inflamma-
tory mediators and reactive oxygen species [1, 4], leading
to macro- and microvascular spasm, microthrombosis,
blood–brain barrier disruption, impairment of cerebral
autoregulation and waves of cortical spreading depolari-
zations, culminating in cerebral ischemia and infarction
[20]. The volume of subarachnoid and intraventricular
blood are the most important predictors of DCI [22, 23].
Despite significant evolution in the understanding of DCI
pathophysiology, vasospasm affecting cerebral vessels of
large and moderate diameter, and consequent perfusion
deficits on CT perfusion imaging, remain the only clini-
cally measurable components of DCI, and thus, the pri-
mary targets for intervention.
Available Evidence
Medical Management of DCI
The primary goal when managing DCI is to optimize
and maintain adequate cerebral perfusion and prevent
cerebral infarction. Interventions that have been used
in DCI prevention [15, 24, 25] include oral nimodipine
(supported by randomized controlled trial [RCT] evi-
dence) [15–17], reduction of subarachnoid blood volume
by aggressive drainage of cerebrospinal fluid [26–28],
optimization of intravascular volume status [29–31] and
hematocrit [32, 33]. Medical rescue interventions for
DCI that have been described in the literature include
hemodynamic augmentation by inducing hypertension
[34–36] or enhancing cardiac output [37], continuous
intravenous milrinone infusion [38, 39] and intraven-
tricular nicardipine [40–42] (Fig. 1).
Hemodynamic Augmentation
Hemodynamic augmentation using vasopressors and
inotropes is considered the first line medical rescue
intervention for DCI [24, 25], despite limited evidence
supporting its use [43] and significant variability across
different centers [9, 44]. The HIMALAIA trial, the only
RCT assessing efficacy of blood pressure augmentation,
failed to demonstrate improvement in functional out-
comes, with more complications in the induced hyper-
tension arm [45]. However, 30% of the patients in the
control arm had spontaneous resolution of symptoms
and the trial was terminated early prior to target enroll-
ment, limiting interpretation [45]. In a recent cross-sec-
tional observational cohort study of > 100,000 patients
with SAH, vasopressor use was associated with worse
discharge outcomes, after adjusting for clinical severity
upon admission and hospital complications, although
the indication for vasopressor use was not specified [9].
Given the potential for complications and limited sup-
porting evidence, clinicians should exercise caution with
hemodynamic augmentation, as recommended by the
current Neurocritical Care Society (NCS) guidelines on
SAH management [46].
 Fig. 1  Available bedside medical interventions for delayed cerebral ischemia (DCI). The figure shows available bedside critical care interventions for
prevention and treatment of DCI that have been described in the literature. Yellow bars represent early strategies that may potentially help prevent
DCI and blue bars represent bedside strategies for medical management after DCI onset. Most of the described therapies are based on retrospec-
tive observational studies with limited evidence on impact on outcomes, and, except for nimodipine, none of the other strategies have randomized
controlled trial evidence supporting their use. EVD, external ventricular drain, SAH, subarachnoid hemorrhage

Intravenous Milrinone Infusion Intraventricular Nicardipine Injection

Intravenous (IV) milrinone promotes hemodynamic aug-
mentation through its inotropic effects and also leads
to cerebral vasodilation by its action on intracranial
phosphodiesterase-III receptors. Multiple case series
have shown successful resolution of SAH-related vasos-
pasm with intravenous milrinone infusion [47–50]. In a
study conducted by Lannes et  al. [51], 88 patients with
SAH who developed DCI were treated with a protocol
combining continuous IV milrinone infusion, with res-
cue intraarterial (IA) milrinone as needed for refractory
DCI. Favorable functional outcome (defined as modified
Rankin Scale [mRS] 0–2) occurred in 75% of the patients.
However, majority of these patients had low-grade SAH
and also received norepinephrine for induced hyperten-
sion, making it difficult to delineate if improved outcomes
were related to milrinone alone [51]. In a follow-up study
involving 322 patients with predominantly high-grade
SAH, who received IV milrinone infusion (dosage 0.25–
2.5 mcg/kg/min) after DCI onset, only 21% developed
DCI-related cerebral infarction and only 19% needed
ERT [52]. Although, this was an observational study
without a control group, this cohort, that was comprised
of a majority of patients with high-grade SAH, also expe-
rienced favorable functional outcomes in 65%, highlight-
ing the potential benefit of IV milrinone. In a before-after
controlled observational study, in which patients with
SAH treated with IV milrinone infusion were compared
with historical controls that did not receive milrinone, a
significantly lower need for ERT, lower occurrence of cer-
ebral infarcts and higher proportion of good functional
outcomes (mRS 0–1) were noted in the IV milrinone
group [39]. However, findings were confounded by lack
of adjustment for temporal improvement in SAH care
between historical controls (2014) and the intervention
group (2020).
Serial intraventricular nicardipine injections into an
external ventricular drain for prevention and treatment
of DCI has been described in retrospective observational
case series and small cohort studies [40–42, 53, 54]. In
a recent systematic review including 377 patients with
SAH who received 6,596 injections of intraventricular
nicardipine, the most commonly described dosage was
4  mg injected every 8–12  h for a variable duration [55].
Intraventricular nicardipine appeared to be safe, with an
overall infection rate of 6%, similar to expected exter-
nal ventricular drain–related infection rates described
in prior literature [55]. TCD velocities improved by a
mean of 26.3  cm/s after intraventricular injections and
the duration of effect lasted for > 24  h with serial injec-
tions [40]. However, microvascular cerebral blood flow
response to intraventricular nicardipine is variable and
a robust improvement in microvascular cerebral blood
flow on diffuse correlation spectroscopy is associated
with reduced occurrence of DCI [56]. In a retrospec-
tive, propensity score matched analysis of 422 patients
treated with intraventricular nicardipine, TCD veloci-
ties improved by 77%, and intraventricular nicardipine
use was associated with reduced odds for DCI as well as
increased odds for good functional outcomes (mRS 0–2)
in the long term [42]. However, no prospective clinical
trials have evaluated safety and efficacy or the impact
on clinical outcomes, limiting its routine use in clinical
practice.
Medically Refractory DCI
Persistence of neurologic deficits despite hemodynamic
optimization is known as medically refractory DCI [15].
The prevalence of medically refractory DCI is unknown.
Nonetheless, ERT plays a significant role in the manage-
ment of these patients [15, 24, 25, 57].
Endovascular Approach to Management of Medically
Refractory DCI
Although no RCTs have assessed the impact of ERTs on
outcomes after SAH, they are used ubiquitously in clini-
cal practice and have been recommended by the Amer-
ican Heart Association (Class IIa, level B) [24], and the
NCS [25] (moderate quality of evidence, strong recom-
mendation) guidelines a decade ago. These recommen-
dations are based on expert consensus, largely stemming
from reviews of retrospective cohort and case–con-
trol studies. ERTs target macrovascular vasospasm and
include transcatheter IA infusion of vasodilators and per-
cutaneous transluminal balloon angioplasty (PTBA) [24,
25, 57, 58].
Triggers for ERT for DCI
The 2011 NCS guidelines for SAH management recom-
mended ERTs for DCI in patients that are refractory to
medical management [25]. They did not provide specific
recommendations on the timing of intervention [25] and
recommended against prophylactic use of ERT [25]. The
2023 NCS guidelines for the neurocritical care manage-
ment of aneurysmal SAH indicate that there was insuf-
ficient evidence to provide a recommendation on the
optimal trigger for ERTs in DCI treatment (change in
neurological exam plus findings on advanced neuroimag-
ing versus change in examination alone) [46].
Due to the lack of specific guidelines, there is incon-
sistency in triggers for ERTs in DCI. International and
national surveys reported that > 90% respondents pur-
sued ERTs only in patients showing clinical signs in com-
bination with sonographic/angiographic vasospasm and
only after failure of maximal medical management [59,
60]. However, use of ERT based on angiographic findings
alone was more common in the United States [59, 60].
Thus, in general, ERTs are instituted when patients with
SAH meet the definition of DCI and have failed to dem-
onstrate sustained neurological improvement with medi-
cal management (Table 1). ERTs may be pursued earlier
in patients unable to tolerate vasopressors/inotropes,
such as with underlying heart disease, decompensated
heart failure, myocardial ischemia, arrythmias, pulmo-
nary edema and unsecured aneurysms. In patients with
high-grade SAH who have a poor neurological examina-
tion at baseline, detection of DCI by clinical examina-
tion is limited. In these patients, the use of multimodality
monitoring tools such as TCD (rising velocities, veloci-
ties ≥ 180–200  cm/s, Lindergaard ratio > 6), continuous
quantitative electroencephalography (asymmetric decline
in alpha:delta ratio and alpha variability), braintissue oxy-
gen tension (­PbtO2) monitoring (asymmetric decline in
­PbtO2 below 15–20  mm Hg) and cerebral microdialysis
Table 1  Triggers for ERT in DCI
Triggers for ERT for DCI:
(Must meet A and B or A and C)
(A) Evidence of ongoing cerebral ischemia (I, or II + III)
I. Clinical:
Drop in GCS by greater than 2 points, not explained by other factors
New focal neurological deficit (aphasia, motor weakness, neglect, hemia-
nopia, gaze deviation)
II. Neurophysiological (in absence of a reliable clinical examination):
Sudden asymmetric decline in alpha-to-delta ratio and/or alpha variabil-
ity on quantitative EEG
TCD with elevated velocities (mean flow velocities > 150 cm/s)
Decline in P ­ btO2 to less than 15–20 mm Hg
Rising lactate:pyruvate ratio (> 40) and/or low cerebral microdialysate
glucose
III. Radiological: (confirmatory: needed if relying only on neurophysiological
assessments to confirm DCI):
CT angiogram with evidence of vasospasm
CT perfusion study with perfusion deficits (low CBF, increased MTT and
TTP)
(B) No sustained neurological improvement with maximal medical man-
agement (as outlined below):
Induced hypertension (MAP or SBP raised by 20 mm Hg; SBP up to
220 mm Hg, MAP up to 140 mm Hg)
Cardiac output augmentation (Cardiac index > 4.0 with inotropes)
Euvolemia and hemoglobin optimization (goal > 10 g/dl)
OR
(C) Inability to tolerate medical therapy:
Congestive heart failure, particularly if decompensated
Acute renal failure with oliguria
Severe pulmonary edema/ARDS
Unsecured aneurysm
ARDS acute respiratory distress syndrome, CBF cerebral blood flow, CT computed
tomography, DCI delayed cerebral ischemia, EEG electroencephalogram, ERT
endovascular rescue therapies, GCS Glasgow Coma Scale, MAP mean arterial
pressure, MTT mean transit time, PbtO2 brain tissue oxygen tension, SBP systolic
blood pressure, TTP time to peak
(signs of energy failure such as rising lactate:pyruvate
ratios and/or low interstitial glucose) may be used to
identify DCI [25]. However, signs of cerebral ischemia
on multimodality monitoring is often confirmed with
sonographic/angiographic evidence of vasospasm and
evidence of hypoperfusion on CT perfusion [21]. Recent
case series have demonstrated successful patient selec-
tion using such tools and improvement in multimodality
markers of cerebral ischemia after ERT [61, 62].
Clinical Practice Variability
Intracranial vasorelaxation using IA vasodilator infusions
are a prevalent approach for refractory DCI, despite the
lack of RCTs [63], leading to significant practice variabil-
ity across the United States and the world [9, 64]. Based
on an intercontinental survey, ERT use was far more
common in the United States compared with other coun-
tries (91% vs. 60%) [64]. In another survey from 32 coun-
tries, IA pharmacotherapy was the most common first
line ERT for refractory DCI; however, there was signifi-
cant variability in the choice of agents, with IA verapamil
(56%) being most common in the United States and IA
nimodipine (74%) outside the United States [59]. A
national survey of neurosurgeons also confirmed signifi-
cant variability, with the most common IA vasodilators
being verapamil (55%), nicardipine (26%), fasudil hydro-
chloride (7%) and milrinone (4%) [60]. There are no high-
quality studies that compare the efficacy of these agents
or the appropriate dosage, leading to additional dispari-
ties in dosage, frequency of interventions, and conse-
quently, degree and durability of response [59, 60].
PTBA, a more durable therapy for DCI, involves
mechanical dilation of stenotic vessels using a balloon.
Similar to IA pharmacotherapy, lack of guidelines has led
to significant variability with respect to PTBA use in DCI
[9, 64]. In an international survey, 91% U.S. and 83% non-
U.S. respondents, reported using PTBA as ERT for DCI
[59] and 95% used it as a second line intervention, after
IA pharmacotherapy [60]. PTBA is generally reserved for
proximal vasospasm, however PTBA for distal vasospasm
(A2, M2, P2 branches and beyond) has been reported
more commonly in the United States [59]. Nonetheless,
majority survey respondents across the world agreed that
PTBA is the most effective ERT, providing superior out-
comes, particularly in combination with IA vasodilators
[59, 60].
Clinical Benefit from Rescue Therapy
The best evidence on the impact of diverse patient risk
factors on functional outcomes and the benefit of ERT
stems from a recent analysis of the Subarachnoid Hem-
orrhage International Trialists (SAHIT) data repository
project [65]. The SAHIT data repository contains patient-
level data from nine clinical studies [66–75], and investi-
gators applied game theory-based methods in explainable
machine learning (ML) and propensity score matching
to determine whether ERT was associated with better
3-month outcomes following post-SAH vasospasm [65].
Rescue therapy was documented as either ERT (PTBA
and IA pharmacotherapy) or noninterventional (includ-
ing induced hypertension, hypervolemia, or hemodilu-
tion). In this analysis, that included 1532 patients with
angiographic vasospasm or DCI, predictive, explainable
ML models revealed that shorter time from SAH onset
to admission, White race, diffuse thick SAH, lack of cer-
ebral edema, greater number of medical diagnoses in
the medical record and prophylactic phenytoin use car-
ried the highest relative importance rankings in predict-
ing whether rescue therapy was administered, reflecting
practice patterns and not necessarily specific indications
for ERT. Younger age and absence of cerebral ischemia/
infarction were invariably linked to better rescue ther-
apy outcomes, whereas the other important predictors
of outcome varied by rescue type (ERT or noninterven-
tional). For example, lower blood pressures and a greater
number of postoperative days until vasospasm treat-
ment were more important for predicting good 3-month
Glasgow Outcome Scale (GOS) scores (defined as 4–5)
following ERT compared to noninterventional rescue.
In propensity score-matched analysis, which included
cohorts of 385 patients each, rescue therapy was asso-
ciated with higher odds of 3-month GOS scores of 4–5
(OR 1.63, 95% CI 1.22–2.17) [65]. Despite these encour-
aging results, this study has important limitations that
are worth highlighting. (1) Although drawing from mul-
tiple sources of high quality clinical data may increase
the power of the analyses, most individual studies had
defined inclusion criteria, which could limit the external
validity of these findings. (2) Limiting the analysis to only
data available within the clinical data sets could prevent
detection of other factors that influence ERT decisions
and outcomes. (3) The included studies were conducted
across many years, which could mean that temporal
changes in SAH management and clinical practice over
time may have influenced the results. (4) A selection bias
may have impacted the results of these studies based on
indications for which the patients received rescue thera-
pies for DCI.
Additional evidence supporting ERT was reported by
the largest cross-sectional observational cohort study in
SAH to date, spanning 10 years (2009–2018) and includ-
ing > 100,000 patients with SAH included in a multi-
center health care analytics database comprising data
from > 95% of U.S. academic medical centers [9]. In this
study, ERTs were associated with reduced odds for hos-
pital mortality as well as poor functional outcomes at
discharge after adjusting for age, clinical severity upon
admission, year of admission, comorbidities, hospi-
tal complications and aneurysmal repair methods [9].
There was significant variability in ERT use across differ-
ent U.S. regions and IA pharmacotherapy (8–12%) was
significantly more common when compared to PTBA
(3%) [9]. While admission clinical severity was taken
into account, it is important to highlight that this study
did not adjust for SAH-specific severity grades (such as
the World Federation of Neurological Surgeons grade or
modified Fisher scale). Additionally, functional outcomes
were assessed using a previously validated nationwide
inpatient sample-based outcome measure (nationwide
inpatient sample-SAH outcome measure [NIS-SOM])
specifically designed for patients with SAH; however,
the study did not evaluate traditional outcome measures
such as mRS or GOS. Nonetheless, NIS-SOM has been
shown to have excellent correlation with poor functional
outcome when defined as mRS 4–6 [9].
Transcatheter Intraarterial (IA) Vasodilator
Pharmacotherapy
Indications for IA Pharmacotherapy
Based on survey studies, IA pharmacotherapy is regarded
as the first line ERT in medically refractory DCI, due to
its relatively lower risk of complications [60]. Patients
with clinical signs of DCI along with sonographic/angio-
graphic evidence of vasospasm are generally considered
for IA pharmacotherapy, after failure of medical man-
agement [59, 60, 64]. Specifically, IA pharmacotherapy
is preferred in patients with mild ormoderate proximal
vasospasm (grade I [0–25% narrowing] and grade II [26–
50% narrowing]), vasospasm involving distal vasculature
(beyond the first branching point of major intracerebral
arteries), proximal segments of anterior (ACA) and pos-
terior cerebral arteries (PCA) and in patients with diffuse
vasospasm [76].
General Technique
There is no specific guidance on appropriate techniques
for IA pharmacotherapy in DCI. The Society of Neuro-
interventional Surgery (SNIS) provides general recom-
mendations on the standards for neurointerventional
procedures [77]. General anesthesia or conscious seda-
tion may be used, depending on patient tolerability, but
patient immobility may be important for better visualiza-
tion of cerebral vasculature [78]. Transarterial approach
using a micro-puncture technique, with the smallest
sheath possible, through the femoral, radial or rarely
carotid arteries may be used [77]. Often, intraproce-
dural anticoagulation with intravenous heparin may be
used prior to accessing intracranial vessels [79]. A flex-
ible guiding catheter is often threaded through the sheath
to first obtain a diagnostic angiogram to assess the loca-
tion and degree of vasospasm. Based on location, an
over-the-wire guide catheter may be advanced into the
proximal carotid or vertebral arteries, and the vasodila-
tor medication may be infused into the vessels. For select
cases of distal middle cerebral artery (MCA) or ACA
vasospasm, a microcatheter may be advanced through
the guide catheter and parked proximal to the stenotic
segment to infuse the pharmacological agent. While
vasodilator agents are being infused, strict monitoring
of the blood pressure may be warranted to avoid sudden
hypotension. If an intracranial pressure (ICP) monitor
is available, monitoring ICP may also be helpful, given
the risk of transient intracranial hypertension after IA
pharmacotherapy.
Mechanism of Action
All IA pharmacotherapeutic options for DCI are arterial
vasodilators that target different receptors on the vas-
cular smooth muscle cells, promoting vasodilation. We
summarize in Table  2 the commonly used agents along
with their mechanisms of action, durability of effect, and
adverse events.
Clinical Response to IA Pharmacotherapy
Several observational studies have described radiologi-
cal response, and some have also described the degree
of neurological improvement after IA pharmacotherapy.
Rates of radiological response, clinical response, delayed
cerebral infarction, good functional outcome with indi-
vidual IA vasodilators are summarized in Table 2. In the
largest and most recent meta-analysis of 55 observational
studies describing response to IA pharmacotherapy (total
sample = 1571 patients), the mean weighted probabil-
ity of immediate angiographic improvement across all
vasodilators was 89% [80]. Of the 55 studies included in
this meta-analysis, 33 reported on neurological improve-
ment and 37 reported clinical outcomes. The probabil-
ity of neurological improvement, defined as resolution
of “vasospasm-related neurological deficits” within 24  h
of IA pharmacotherapy, was 57% [80], indicating that
while angiographic response to IA pharmacotherapy
is robust, it may not always translate into neurologi-
cal improvement. This may be due dissociation between
angiographic vasospasm and cerebral ischemia described
above [18]. More recent observational studies have also
demonstrated neurological improvement after IA phar-
macotherapy in more than 50% [81, 82]. Very few studies
have compared IA pharmacotherapy with control groups,
and in pooled analysis of a small number of such studies,
outcomes did not differ between IA pharmacotherapy
and medical management [80].
With respect to individual vasodilators, observa-
tional studies have shown most robust angiographic
improvement with fasudil, verapamil and nicardipine
(mean probabilities: 96–99%) [80]. This contrasts with
survey studies, in which clinicians reported observing
angiographic improvement in a lower proportion of
patients overall (60–70%), with the best response with
IA nimodipine (not available in the United States) and
worst with IA verapamil [59, 60]. In a meta-analysis,
the highest probability of neurological improvement
within 24  h of infusion were seen with nicardipine
(74%), nimodipine and fasudil (60–65%), while for good
clinical outcome, best results were seen with milrinone
(72%), nicardipine, nimodipine and fasudil (65–67%)
[80]. New ischemic lesions on delayed neuroimaging
were most common with IA papaverine (52%) and least
common with nimodipine (23%) and verapamil (25%)
[80]. Although verapamil promoted good angiographic
response, the mean probabilities of neurological
improvement (38%) and good clinical outcome (46%)
were significantly lower [80]. In another observational
Table 2  Comparison of intraarterial vasodilators for delayed cerebral ischemia
Vasodilator Mechanism of action Angiographic Clinical Delayed cer- Durability of response Side effects Good
response (%) response ebral infarction ­outcomea
(%) (%) (%)

Papaverine Nonselective vasodila- 87 46 52 Short; 12-h?; re- ICP elevation 66

tor; acts by inhibiting treatment needed in Hypotension
cAMP and cGMP in 34–54% Mydriasis
smooth muscles Papaverine crystalliza-
tion with heparin:
distal embolism
Neurotoxicity from BBB
disruption
Thrombocytopenia
Cardiac toxicity
Nimodipine Dihydropyridine 70 60 23 24–48 h Hypotension 65
Calcium channel Bradycardia
blocker; lipophilic,
thus crosses BBB
Nicardipine Dihydropyridine cal- 96 74 30 Longer; up to 96 h? Hypotension 67
cium channel blocker Tachycardia
Verapamil Nondihydropyridine 96 38 25 Shorter, re-treatment Hypotension 46
calcium channel needed in 34–54% Bradycardia
4
blocker Transient ­ICP elevation
(with higher doses)
Milrinone Phospho-diesterase 100 76 21 Unclear; 23% may Hypotension (15%), 75
III inhibitor; inhibits require re-treatment severe hypotension
cAMP and myosin in 48-h (2.4%)
light chain kinase Myocardial ischemia
Arrythmias
Fasudil Rho-kinase inhibitor 99 66 31 Unclear Transient Hypotension 66
(involved in cerebral Mild ICP elevation
vasospasm); inhibits
action of free intracel-
lular calcium ion,
myosin light chain
kinase and protein-
kinase 3 leading
to smooth muscle
relaxation
BBB blood–brain barrier, cAMP cyclic adenosine monophosphate, c-GMP, cyclic guanosine monophosphate, ICP intracranial pressure, mRS modified Rankin Scale
a
  Good outcome was defined as mRS 0–2 or Glasgow Outcome Scale of 4–5

study, 76% of patients receiving IA milrinone experi-
enced neurological improvement within 24 h [52].
Studies have suggested better results with a more
aggressive approach to IA pharmacotherapy. Using a
combination of multiple IA vasodilators simultane-
ously, rather than a single agent infusion, provided
superior response with respect to functional outcomes
at discharge and 90 days in a small observational study
[83]. A large retrospective cohort study of 1057 patients
with SAH, compared a conservative versus liberal ERT
approach for DCI treatment [84]. Despite no differ-
ences in baseline characteristics, the group of patients
who received more frequent ERT (25% vs. 14%) with
early initiation (defined as the first treatment on post-
bleed day 6 vs. first treatment on post-bleed day 9), had
significantly lower rates of DCI (21% vs. 30%) and unfa-
vorable outcome (44% vs. 51%) [84].
Adverse Effects of IA Pharmacotherapy
Most adverse effects of IA pharmacotherapy are transient
and represent a direct consequence of the pharmacologi-
cal effects of the medication. Common adverse effects
of IA vasodilators are summarized in Table  2. Intrapro-
cedural hypotension shortly after the IA infusion is the
most common adverse effect, but is often short lived and
can be corrected with vasopressors, although refractory
hypotension has been reported with IA nicardipine and
IA nimodipine. In a case series of 25 patients treated with
IA nimodipine, the mean systolic blood pressure (SBP)
dropped by 18  mm Hg during the procedure [85]. In
another series of 11 patients treated with IA nicardipine,
SBP dropped by > 21% in up to 50% [86]. Similar findings
were noted with fasudil and verapamil. IA milrinone may
have less effects on BP [87], although severe hypotension
may occur in 2.4%, and may increase risk of myocardial
ischemia, and arrythmias [52].
IA vasodilators may also lead to intracranial hyper-
tension due to cerebral vasodilation in the setting of
impaired cerebral autoregulation and reduced intrac-
ranial compliance due to blood volume and cerebral
edema. This may be particularly relevant in patients
with an elevated ICP at baseline. In patients receiving
IA papaverine, those that had a baseline ICP of < 15 mm
Hg prior to IA infusion, did not develop significant
ICP elevation after vasodilator infusion [88]. ICP ele-
vation is particularly more common with IA papaver-
ine, given its nonselective vasodilatory effects leading
to increased intracranial venous blood volume, and is
therefore associated with worse outcomes [87]. There
are reports of transient ICP elevation with other arte-
rial vasodilators, but clinical significance is unclear. A
higher dose of IA verapamil (> 20 mg) is associated with
sustained ICP elevation and cerebral perfusion pressure
reduction for up to 6 h after the procedure, but this did
not translate into brain tissue hypoxia or energy failure,
suggesting that despite ICP elevation, brain metabolism
is preserved due to improved cerebral perfusion after
IA pharmacotherapy [89].
IA papaverine has several other side effects, including
mydriasis, visual disturbances, cardiotoxic effects, and
thrombocytopenia. Additionally, papaverine may crys-
tallize when infused along with heparin, which can lead
to distal embolism and cerebral infarcts. Papaverine
may have neurotoxic side effects and can disrupt the
blood–brain barrier. Due to these reasons, along with
availability of newer agents with better tolerability, IA
papaverine has fallen out of favor [87].
Pros and Cons of IA Pharmacotherapy
IA pharmacotherapy has several benefits, requiring lesser
skills, lower risk of life-threatening complications such
as vessel rupture, and better access to distal vasculature
(Table 3). However, durability of the therapeutic response
is limited, and varies depending on the vasodilator. In
most studies, durability has been measured using surro-
gates of cerebral blood flow, such as TCD velocities, or by
the need for repeat endovascular interventions. In stud-
ies using IA papaverine or IA verapamil, repeat endovas-
cular intervention was required in 34–54% [90, 91]. Older
age and initial use of angioplasty in combination with the
IA infusion were associated with reduced odds for repeat
ERT [91]. Thus, while IA pharmacotherapy may be the
preferred first choice due to its safety profile, contin-
ued monitoring after IA pharmacotherapy is warranted,
as repeat endovascular infusions may be needed. Some
studies have suggested maintaining a microcatheter in
the cerebral arteries with continuous vasodilator infu-
sions to prevent recurrence [92]; however, this strategy
may be associated with arterial thromboembolic events.
Percutaneous Transluminal Balloon Angioplasty
(PTBA)
Indications for PTBA
In survey studies most clinicians agree that PTBA is the
most effective therapy for medically refractory DCI, but
due to associated risks it is often reserved as a second
line intervention, if no response is noted to IA pharmaco-
therapy [59, 60]. PTBA is used in severe focal vasospasm
(grade III [50–75%] and grade IV [> 75%]) [76] involv-
ing proximal intracranial vessel segments, such as dis-
tal internal carotid (ICA), MCA (M1segment), proximal
ACA, proximal PCA, vertebral and basilar arteries [93].
A minimum vessel diameter of 2.0–2.5 mm is considered
appropriate for PTBA [94, 95]. However, observational

Table 3  Differences in features of treatment between intraarterial pharmacotherapy and cerebral angioplasty

Factors Intraarterial vasodilators Cerebral angioplasty

Mechanism of action Pharmacological dilation of vessels by promoting vascular Mechanical dilation of vessels with balloon, by promot-
smooth muscle relaxation ing disruption of internal elastic lamina and altering
myocytes
Type of vessel targeted Can be used for proximal and distal vessels; less benefit Reserved for proximal vessels; may be used in distal ves-
with severe vasospasm in proximal vessels sels with caution; more beneficial in severe proximal
vasospasm
Angiographic response Variable, depends on agent; ranges from 70 to 100% Good in nearly 100% of reported cases
Clinical response Variable, depends on agent; ranges from 40 to 76% Variable, around 60%
Favorable functional outcome Variable, depends on agent; Reported in 70–80%
Ranges from 46 to 75%
Durability of response Low May last entire vasospasm period
Safety Transient complications may occur, but low likelihood of Good, but 5% chance of severe vascular complications that
life-threatening complications can be life-threatening
studies have also demonstrated excellent response with
distal vasospasm, with an overall low risk of vascular
complications, particularly with the use of calibrated
balloons that decrease risk of vessel rupture [95, 96].
The Balloon Prophylaxis of Aneurysmal Vasospasm
study, a phase II trial randomly assigning patients with
SAH to prophylactic PTBA within 96  h versus standard
medical care, demonstrated a trend toward reduction
in DCI-related infarction and neurological deficits [97].
However, four patients had catastrophic vessel rupture,
of whom three died [97]. Based on these findings, pro-
phylactic PTBA is not recommended per the 2011 NCS
guidelines [25]. It is important to note that this study was
conducted more than a decade ago, and newer balloon
designs may be safer, although this needs further inves-
tigation. In summary, PTBA may be indicated primarily
in DCI related to proximal focal vasospasm, that does
not improve with IA pharmacotherapy, or recurs soon
after, and can be used cautiously in patients with distal
vasospasm.
General Technique
Generally, PTBA follows IA pharmacotherapy, which
may be needed to dilate severely spastic vessels before
inserting the balloon catheter into the vessel. The size
of the balloon chosen may be contingent upon the tar-
get vessel diameter, which is often assessed using imaging
prior to vasospasm onset [94]. Oversized balloons can
lead to vessel rupture.
Additionally, single lumen balloons are more compliant
and carry less risk of vessel rupture, but double lumen
balloons provide technical advantage when maneuvering
the wire and balloon into vessels with acute angulation,
as in such cases, the wire may be withdrawn to reshape
Fig. 2  Angiographic response to percutaneous transluminal balloon angioplasty. a Catheter angiogram, showing severe focal spasm supraclinoid
ICA. b Roadmap while angioplasty (single lumen balloon) is performed showing homogeneous inflation with an elongated balloon. c Catheter
angiogram immediate post balloon angioplasty, showing significant improvement at the stricture. Good outcome was defined as mRS 0–2 and/or
GOS 4–5. ICA, internal carotid artery, mRS, modified Rankin Scale
its tip without moving the balloon from its location [98].
After the catheter is advanced past the stenotic segment,
stepwise graded inflations may be performed. Prior pub-
lications have suggested a maximum of three inflations
for ≤ 10  s each per vessel segment [93], and have sug-
gested submaximal inflation, targeting dilation smaller
than the prevasospastic arterial caliber, to prevent ves-
sel rupture. For long segment stenoses, the balloon may
be inflated in the distal portion of the stenotic segment,
then deflated and withdrawn proximally and then rein-
flated again until the entire vessel segment is mechani-
cally dilated [94]. Follow-up angiograms can provide into
the angiographic response to the procedure after each
treatment (Fig.  2), to determine whether second line
interventions such as another vasodilator or angioplasty
may be needed [76, 77, 79]. General anesthesia may be
more preferable in patients receiving PTBA, given risk
of intraprocedural vascular complications. Limited evi-
dence guides physiologic goals during PTBA similar to
IA pharmacotherapy, but after successful angioplasty, the
SBP may be lowered to prevent reperfusion injury.
Mechanism of Action
PTBA is believed to promote vasodilation by mechanical
stretching of the vascular endothelium, internal elastic lam-
ina and alteration of vascular myocytes. In an experimen-
tal SAH primate model, post-angioplasty vessel histology
revealed endothelial denudation, dehiscence of the internal
elastic lamina and deformation of myocytes [98]. Canine
models demonstrated functional alteration in tunica media
myocytes after PTBA, that lasted for up to 3  weeks after
treatment, supporting the clinical observation that PTBA
induced long lasting vasodilation [99]. In post-mortem
pathological analysis of human cerebral vessel walls after
PTBA, findings confirmed stretching of extracellular
matrix, tunica media, disruption of internal elastic lamina,
intramural hemorrhages and increased collagen and myo-
cytes in the extracellular matrix [100]. This alteration in
vascular tunica media and tunica adventitia is responsible
for the more definitive and durable response noted with
PTBA, and it also contributes to the associated vascular
complications, such as dissection and vessel rupture.
Clinical Response to PTBA
PTBA is associated with favorable radiological and clini-
cal results in most reported uncontrolled case series.
In a case series of 14 patients with SAH with refractory
vasospasm, xenon-enhanced CT imaging demonstrated
a mean increase in cerebral blood flow by 31  ml/100  g
brain tissue/minute after PTBA and 92% patients had
neurological improvement, with 58% showing com-
plete resolution of neurological deficits [101]. In a larger
observational study of 116 patients with DCI receiving
PTBA and IA nicardipine, nearly all patients demon-
strated immediate angiographic improvement, 60% dem-
onstrated neurological improvement within 24–48  h of
procedure, 73% had a favorable functional outcome at
discharge, and only 26% had radiographic cerebral infarc-
tion [102]. Other case series and observational studies
have also reported similar response rates with PTBA [93,
103–105]. Figure 2 shows an example of excellent angio-
graphic response to PTBA.
Factors independently associated with poor functional
outcome after PTBA include higher SAH grade, presence
of hypodensities prior to the procedure, posterior circu-
lation aneurysms, and lack of neurological recovery after
PTBA [102]. Timing of PTBA after DCI onset may also
influence the clinical response. In a retrospective case–
control study of patients with SAH with refractory DCI,
70% of those that received PTBA within 2 h of symptom
onset had immediate neurological improvement, ver-
sus only 40% in the group that received PTBA > 2 h after
symptom onset [106]. Another factor contributing to
successful resolution of angiographic vasospasm may be
the location of the stenotic segment. Among 75 patients
with severe refractory vasospasm, PTBA resulted in suc-
cessful resolution of angiographic vasospasm in 100%
patients with distal ICA vasospasm, 94% with proximal
MCA vasospasm, 73–88% with vertebrobasilar vasos-
pasm, but only in 34% with ACA vasospasm [105]. Simi-
larly, delayed cerebral infarction was far more common in
ACA territories than MCA territories treated with PTBA
(38% vs. 7%) [107]. This may, at least in part, be related
to the acute angulation of the ACA, making it difficult to
achieve good mechanical dilatation.
Response with PTBA may last through the entire
vasospasm period in the treated vessel segment [94].
In a study that compared PTBA to IA papaverine, re-
treatment was needed only in 1% of the vessel segments
treated with PTBA, but in 42% of those treated with IA
papaverine [108]. In a small study of 32 patients receiv-
ing PTBA for distal vasospasm, re-treatment was needed
in only 8% [96]. Likewise, when PTBA was compared to
IA milrinone for distal vasospasm, delayed infarction
(2.2% vs. 7.5%) and re-treatment were significantly less
common with PTBA (8% vs. 19%), but outcomes did not
differ significantly, with up to 80% achieving good func-
tional outcome in both groups [95]. Other studies have
reported higher rates of re-treatment after PTBA, in up
to 20% [93, 102], although vascular segments re-treated
distal to the previously vasospastic segments were also
included in the definition of re-treatment [94]. Likewise,
some other studies suggest that up to 16–40% of the same
vessel segments treated with PTBA may need re-treat-
ment for recurrent vasospasm [93, 109]. Need for repeat
ERT (IA pharmacotherapy or PTBA) is more common in
patients with higher SAH grade, ACA vasospasm, distal
vasospasm, multivessel vasospasm, and in patients who
only received IA vasodilators as initial treatment [102,
109].
Adverse Effects/Complications
Several potentially life-threatening and debilitating com-
plications may occur in in up to 5–6% of patients treated
with PTBA [109, 110]. The most dangerous is vessel rup-
ture, that is directly related to balloon inflation, and often
fatal. Vessel rupture with PTBA has been reported in 1%
of patients [103, 104, 108, 110] and can be prevented by
using appropriate balloon size, calibrated balloons and
avoiding PTBA in smaller diameter vessels that have a
thin tunica media and higher risk of rupture. Thrombo-
embolic complications directly related to PTBA may also
occur in 5% of patients [105]. However, overall, occur-
rence of vascular complications in majority of small
cohort studies evaluating PTBA was very low [96]. Other
complications, bedsides vascular access site-related com-
plications, include reperfusion injury, intracranial arterial
dissection, displacement of surgical clips, and aneurys-
mal rupture [87].
Practice Guidance
Medical rescue therapies and ERTs are an important
component of DCI management in patients with SAH,
despite lack of randomized clinical trial evidence. Based
on available evidence and common practices, we sum-
marize a reasonable approach to management of DCI.
Patients with aneurysmal SAH should receive continu-
ous neurological monitoring and patients with a poor
neurological examination to follow may also benefit
from ancillary testing such as serial TCDs or continuous
quantitative electroencephalogram monitoring to detect
DCI. In patients who have a reliable clinical examination
to follow, DCI therapies may be instituted when there is
a clinical change, characterized by global neurological
decline or a new focal neurological deficit, coupled with
either sonographic or angiographic evidence of vasos-
pasm. In patients who have a poor neurological exami-
nation at baseline, DCI may be suspected when TCD
velocities are markedly elevated or if quantitative electro-
encephalogram monitoring for patients with high-grade
SAH reveals an asymmetric decline in alpha: delta ratio
or alpha variability. In this patient population, however, it
may be prudent to pursue a CT angiogram and CT per-
fusion study to confirm the diagnosis of DCI. Once DCI
is confirmed, hemodynamic augmentation with vaso-
pressors may be pursued as a first line rescue interven-
tion. There is limited evidence to support specific blood
pressure target during the DCI period, and these may be
tailored to the patient’s clinical response (possibly rais-
ing SBP by ≥ 20 mm Hg, until clinical improvement or a
maximum of 220  mm Hg). In those patients in which a
poor baseline clinical examination does not allow detec-
tion of an improvement with hemodynamic augmenta-
tion, ERT should be pursued early. In patients with a poor
neurological examination at baseline, where there are no
parameters to follow for improvement, pursue ERTs may
be pursued early. IA pharmacotherapy, using calcium
channel blockers or IA milrinone may be preferred as
the first line, particularly in patients with diffuse or dis-
tal vasospasm. PTBA may be pursued in patients with
severe proximal vasospasm, such as MCA M1 segments
or distal ICA, if a limited or no response is noted to IA
pharmacotherapy. After treatment, patients should be
closely monitored in the neurocritical care unit through
the entire DCI window. Provided there are no contrain-
dications, hemodynamic augmentation may be contin-
ued intraprocedurally and after the procedure until DCI
resolves. It may be reasonable to maintain euvolemia and
target a hemoglobin level of at least 8 g/dl or more, prior
to and after ERT. Serial re-treatments with IA pharmaco-
therapy could be pursued if there is a new clinical change,
rising TCD velocities and/or CTA/CTP with perfusion
deficits in patients with a poor neurological examination.
In patients who need repeated ERT or in those that are
medically unstable precluding repeated transport to the
endovascular suite, serial intraventricular nicardipine
injections may be considered as an alternative (Fig. 3).
Future Directions
With respect to medical DCI therapies, targeting other
mechanisms of DCI beyond vasospasm, such as cortical
spreading depolarizations and autoregulation, is gaining
interest. Cilostazol, which has been shown to suppress
cortical spreading depolarizations, may be associated
with improved outcomes among patients with SAH [111,
112]. A phase II RCT evaluating the safety and efficacy
of cilostazol plus nimodipine versus placebo on DCI in
patients with SAH is underway (NCT04148105). Addi-
tionally, optimizing cerebral autoregulation using person-
alized blood pressure targets derived using continuous
autoregulation data appears promising [113–116]; how-
ever, feasibility studies and RCTs are warranted before
incorporation into clinical practice.
Thus far, there has been no RCT that has confirmed
the efficacy of ERTs leading to significant variability in
their use across the United States and the world, possibly
impacting outcomes after SAH [9]. Centers offering ERTs
may have superior outcomes when compared to centers
that are unable to offer ERT [117]. In the largest cross-
sectional cohort study of > 100,000 patients with SAH,
ERT use was associated with reduced odds for poor dis-
charge outcomes and propensity score–matched analysis
of the SAHIT repository data indicates that ERTs may be
associated with higher odds for a good clinical outcome
at 3  months [9, 65]. Future research in ERTs for DCI
needs to answer several important clinical questions,
including the optimal triggers for intervention, timing
of treatment, role of prophylactic IA pharmacotherapy,
the most effective agent, appropriate dosage, and fre-
quency of interventions. We also need to understand the
true impact of these therapies on short and long-term
functional outcomes after SAH, and associated adverse
effects. Given the lack of any other effective treatments
for DCI and the significant clinical benefit perceived by
clinicians in survey studies and numerous small observa-
tional studies, an RCT may not be feasible. Comparative
effectiveness research using multicenter large prospec-
tive observational cohorts, with common data elements
and serial standardized measurements of short-term and
long-term functional outcomes as well as patient-cen-
tered outcomes, may help answer these important ques-
tions and further help streamline ERT in DCI.
Conclusions
Despite no RCT data showing benefit, hemodynamic
augmentation remains the first line medical rescue ther-
apy for DCI and ERTs are the mainstay for management
of medically refractory DCI, based on retrospective and
observational studies. IA vasodilator therapy is the first
line intervention in medically refractory DCI and PTBA
is reserved for refractory vasospasm involving proxi-
mal arterial segments. Several questions regarding ERTs
remain to be answered, including triggers, timing of ini-
tiation, role (if any) for early prophylactic IA pharmaco-
therapy, and their impact on outcomes after SAH.
 Fig. 3  Algorithm for endovascular rescue therapies (ERTs) in DCI. The figure shows a suggested algorithmic approach to utilization of ERT for DCI in
clinical practice. *In patients with poor neurological examination at baseline, triggers for initiating treatment can include alterations in neurophysi-
ological parameters on multimodality monitoring tools. DCI, delayed cerebral ischemia, IA, intraarterial, ICA, internal carotid artery, ICU, intensive
care unit, IV, intravenous, MCA, middle cerebral artery, PTBA, percutaneous transluminal balloon angioplasty

Author details Conflicts of interest

1
 Division of Neurosciences Critical Care, Departments of Anesthesiology
and Critical Care Medicine, Neurology, and Neurosurgery, The Johns Hopkins
University School of Medicine, 1800 Orleans Street, Zayed 3014A, Baltimore,
MD, USA. 2 Division of Cerebrovascular and Endovascular Neurosurgery,
Department of Neurosurgery, The Johns Hopkins University School of Medi-
cine, Baltimore, MD, USA.
Author Contributions
VAS conceptualized the manuscript structure, conducted the literature search,
wrote the first draft of the manuscript, and prepared figures and tables. LFG
reviewed and edited the manuscript, wrote the sections on techniques of
intraarterial pharmacotherapy and percutaneous transluminal balloon angio-
plasty, and prepared Fig. 2. JIS conceptualized the manuscript, supervised
the literature search, and performed critical review and editing of the entire
manuscript. The final manuscript was approved by all authors.
Source of Support
This work received no funding.
VAS does not report any conflict of interest for this publication; disclosures
include being a member of the Editorial Board of the journal Neurohospitalist.
LFG does not report any conflicts of interest for this publication. JIS reports no
conflicts of interests for this publication; disclosures include being a member
of the clinical events committee for the REACT Study, which is funded by
Idorsia; member of the Editorial Board of the journal Stroke; ex-officio member
of the Board of Directors of the Neurocritical Care Society.
Ethical Approval/Informed Consent
We confirm adherence to ethical guidelines. No institutional review board
approval was required for this narrative review article.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in pub-
lished maps and institutional affiliations.
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive
rights to this article under a publishing agreement with the author(s) or other
rightsholder(s); author self-archiving of the accepted manuscript version of
this article is solely governed by the terms of such publishing agreement and
applicable law.
Received: 26 March 2023 Accepted: 3 May 2023
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