Stroke

EDITORIAL

Treating Delayed Cerebral Ischemia: Should We

Focus on Blood Pressure or Vasodilatation?
Ofer Sadan , MD, PhD; Feras Akbik , MD, PhD

D
elayed cerebral ischemia (DCI) following sub- From the vasodilatory standpoint, although oral
arachnoid hemorrhage remains a significant clini- nimodipine demonstrated efficacy as early as the 1980s,
cal challenge. Its clinical importance stems from countless lines of inquiry since then have not led to novel
2 distinct features: the significant correlation between therapies. In a recent systematic review, Qureshi et al11
DCI and patient outcomes and its delayed appearance showed that there was no positive phase 3 clinical trial
which allows time for intervention.1,2 The only treatment addressing DCI since the nimodipine ones, although dif-
shown to prevent DCI is oral nimodipine,3,4 and there- ferent interventions were tried to induce vasodilatation,
fore, it is the only level I recommendation in current for example by using different calcium channel blockers,
clinical guidelines.5,6 endothelin receptor antagonists, magnesium, or by oxi-
dative stress reduction.
Even with oral nimodipine, DCI remains a common
See related article, p 2607 complication, and in lieu of other proven interventions,
multiple centers developed off-label rescue treatments.
For some, there is prospective controlled data to support
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DCI often occurs in the settings of cerebral vaso- it (such as intravenous milrinone12 or oral cilostazol13).
spasm and is, therefore, thought to be largely driven by In others, data remains retrospective to the most part
local hypoperfusion,7 although alternative mechanisms (eg, intrathecal nicardipine14). Another common rescue
likely contribute.8 The vasospasm and hypoperfusion the- intervention is the application of intraarterial vasodilators
ory led to 2 different paths of therapy: improving perfu- during angiography, and mechanical interventions such
sion by induced hypertension and alleviating vasospasm as balloon or stent assisted angioplasty.15 These inter-
by inducing vasodilatation, 2 mechanisms which often ventions are limited by invasive nature, short effect, and
counteract one another. procedural risk.16 A combined approached was previ-
Induced hypertension has long been a cornerstone ously described in which the microcatheter is left in one
of therapy for cerebral vasospasm and DCI, originally as or more of the cerebral arteries, while vasodilators such
part of the triple-H therapy (hypertension, hypervolemia, as nimodipine, are infused intraarterially in a continuous
and hemodilution). While some radiological-based ben- fashion for multiple days.15,17
efit was found,9 the triple-H therapy gradually lost its role In the current issue of Stroke, Weiss et al18 published
due to lack of clinical effect on patient outcomes.8 The a retrospective analysis of a pre/post change in their
specific role of induced hypertension remains controver- usual care protocol. In the original clinical protocol, all
sial. On the one hand, anecdotal reports and experience patients with clinical DCI or high-risk patients (for exam-
of transient improvement in clinical status exists, yet on ples those with perfusion deficit on CT-perfusion, or a
the other there is no data to support its use in a continu- significant reduction in partial pressure of brain tissue
ous fashion.10 oxygen—PtiO2) were treated with induced hypertension.

Key Words: Editorials ◼ angiography ◼ blood pressure ◼ brain ischemia ◼ oxygen ◼ perfusion ◼ subarachnoid hemorrhage

The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
Correspondence to: Ofer Sadan, MD, PhD, Department of Neurology and Neurosurgery, Division of Neurocritical Care, Emory University School of Medicine 1354
Clifton Rd NE Atlanta, GA. Email ofer.sadan@gmail.com
For Disclosures, see page 2619.
© 2022 American Heart Association, Inc.
Stroke is available at www.ahajournals.org/journal/str

Stroke. 2022;53:2617–2619. DOI: 10.1161/STROKEAHA.122.039800 August 2022   2617

 Sadan and Akbik Treating Delayed Cerebral Ischemia

Refractory cases were further treated with continuous would be reduced PtiO2. However, if vasocontraction is
intraarterial nimodipine using one or more microcathe- driving the difference in ptiO2, intracranial pressure should
ters left in any of the carotid or vertebral arteries (IAN), be lower in the group treated with higher doses of nor-
Editorial

while maintaining an elevated systolic blood pressure epinephrine due to a reduction in cerebral blood volume.
>180 mm Hg. Given the tension between induced hyper- The authors hypothesized that this discrepancy is related
tension and the hemodynamic effects of a continuous to altered autoregulation in the settings of an acute brain
vasodilator therapy, the authors developed a novel proto- injury such as subarachnoid hemorrhage.
col where the hemodynamic goal was reduced to systolic It is worth considering that the vasoconstrictor effect
blood pressure >120 mm Hg for refractory cases receiv- of norepinephrine is dose dependent. This mixed effect
ing IAN, shifting the weight towards vasodilatation. could be the result of high norepinephrine dose on the
Weiss et al,18 describe that although IAN was locally one hand and causing vasoconstriction, while blunting
administered, it often resulted in hypotension, relative to the β-adrenergic effect on improved cardiac output. The
the standard of care goal of systolic blood pressure >180 combination of highly activated vasoconstricting α-1
mm Hg, or absolute hypotension, related to the systemic adrenergic receptors with the vasodilatory calcium chan-
vasodilatory effects of nimodipine. The reduced blood nel blocker likely results in an effect outside of normal
pressure, compared with the threshold set, required a physiological response. Regardless, prolonged induced
high dose of vasoactive drips (mainly norepinephrine). hypertension in this report was associated with reduced
The authors hypothesized that such high doses of nor- perfusion both based on the intracranial pressure (which
epinephrine may have negative systemic and cerebral is a key component of the cerebral perfusion pressure)
results, which rationalized the change of the blood pres- and tissue oxygen delivery.
sure goal to >120 mm Hg. When assessing clinically relevant patient out-
The primary outcome of this study was to demon- comes, no differences were demonstrated between
strate reduction in norepinephrine use following the pro- the 2 protocols. Specifically, DCI-related infarction and
tocol change, along with overall safety of this regimen. long-term functional outcomes were similar. However,
The secondary outcomes were markers of perfusions interpreting these outcomes is very limited by the small
(namely PtiO2), intracranial pressure, DCI-related infarcts cohort in this report.
and long-term functional outcomes of the patients. Continuous IAN intervention is an aggressive and
The study enrolled a total of 243 subarachnoid hemor- atypical type of rescue therapy. It certainly has advan-
rhage patients over 7 years in a single center. Forty-nine tages. For example, it reduced the need for repeated
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patients developed refractory vasospasm which did not angiographies, and facilitated titration based on dose
respond to induced hypertension and deemed to require and location (placing the microcatheter in certain arter-
IAN. Of the 49 patients, 29 were treated with IAN along ies). Yet, as the authors describe, this approach has
with induced hypertension (old protocol) and 20 with the many limitations as well. Maintaining IAN using micro-
new one without the induced hypertension. The 2 groups catheters that dwell in the main cerebral arteries (carot-
were similar from a demographic standpoint, as well as ids or vertebral) for days requires ongoing sedation,
main risk factors, aneurysm location, and aneurysm oblit- likely to a greater degree compared with patients who
eration approach (surgical versus endovascular). do not have microcatheters in place. It also required a
Unsurprisingly, norepinephrine doses were ≈60% continuous infusion of an antithrombotic agent (tirofi-
lower with lower blood pressure goals. The authors fur- ban in this report), which has its own risks, especially
ther report a similar rate of the study’s defined serious external ventricular drain-associated hemorrhages,
complications (eg, new onset heart failure or renal failure, postoperative bleeds, or spontaneous parenchymal
in about 20% overall), and a lower rate of minor compli- hemorrhages (which were not reported herein). Indeed,
cations in the alternative approach, specifically showing in this cohort by Weiss et al, over 35% of subjects did
a decrease in the rate of peripheral hypoperfusion and not tolerate this intervention. Moreover, the catheters
arrythmias. However, the treatment was not tolerated by malfunctioned in over 20% of cases, and embolic
a similar proportion of patients (51.7% in the induced event related to the microcatheter was documented in
hypertension group versus 35% in the alternative group). 8.1% of the cohort, which are objectively high rates of
For the secondary, efficacy outcomes, the authors complications for any procedure. The thromboembolic
used multimodal monitoring which allowed them to mea- complications occurred above and beyond DCI-related
sure surrogates for cerebral perfusion. Interestingly, the infarcts, the very complication that this intervention
ptiO2 was higher in the group with the lower blood pres- aims to prevent. The rate of complications will likely
sure goal, as well as a lower average intracranial pressure. constrain widespread adoption in the absence of pro-
These 2 results could be contradictory to some degree. spective studies.19 Moreover, the specific use of intra-
Induced hypertension with norepinephrine can cause arterial nimodipine cannot be adopted in the United
cerebral vasoconstriction, and therefore, reduced perfu- States, since its intravenous formation is not approved
sion; therefore, the anticipated result of vasoconstriction by the Food and Drug Administration.

2618   August 2022 Stroke. 2022;53:2617–2619. DOI: 10.1161/STROKEAHA.122.039800

 Sadan and Akbik Treating Delayed Cerebral Ischemia

This study does deliver 2 important messages: first, 6. B BJ, Sander CE, Hunt BH, G DR, E DJ, N DM, E DJ, E HR, B PA, H RR.
Guidelines for the management of aneurysmal subarachnoid hemorrhage.
the clear unmet need to develop effective and safe treat- Stroke. 2009;40:994–1025. doi: 10.1161/STR.0b013e3182587839
ments for patients at high risk for DCI remains; and sec- 7. Wijdicks EFM. Bringing the second event to light (on a light box): cere-

Editorial
ond, the data delivers indirect evidence to the lack of bral vasospasm after aneurysmal rupture [published online March 4, 2022].
Neurocrit Care. 2022. doi: 10.1007/s12028-022-01456-9
effect, and potential harm of continuous induced hyper- 8. Chou SH. Subarachnoid hemorrhage. Continuum (Minneap Minn).
tension for patients with cerebral vasospasm-related DCI. 2021;27:1201–1245. doi: 10.1212/CON.0000000000001052
In the on-going tension between the induced hyperten- 9. Engquist H, Rostami E, Ronne-Engström E, Nilsson P, Lewén A, Enblad
P. Effect of HHH-therapy on regional CBF after severe subarachnoid
sion approach to address cerebral vasospasm induced hemorrhage studied by bedside xenon-enhanced CT. Neurocrit Care.
hypoperfusion and induced vasodilatation, focusing on 2018;28:143–151. doi: 10.1007/s12028-017-0439-y
the local administration of a vasodilator seems to have a 10. Gathier CS, van den Bergh WM, van der Jagt M, Verweij BH, Dankbaar
JW, Müller MC, Oldenbeuving AW, Rinkel GJE, Slooter AJC; HIMALAIA
favorable effect. Although locally administered, the intra- Study Group. Induced hypertension for delayed cerebral ischemia after
arterial approach suffered from a high complication rate aneurysmal subarachnoid hemorrhage: a randomized clinical trial. Stroke.
and systemic adverse events. Further studies are needed 2018;49:76–83. doi: 10.1161/STROKEAHA.117.017956
11. Qureshi AI, Lobanova I, Huang W, Ishfaq MF, Broderick JP, Cassarly CN,
to understand the changing physiology of these compli- Martin RH, Macdonald RL, Suarez JI. Lessons learned from phase II and
cated patients, to select the appropriate treatment, for phase III trials investigating therapeutic agents for cerebral ischemia
the appropriate patient, at the appropriate time. associated with aneurysmal subarachnoid hemorrhage. Neurocrit Care.
2022;36:662–681. doi: 10.1007/s12028-021-01372-4
12. Abulhasan YB, Ortiz Jimenez J, Teitelbaum J, Simoneau G, Angle MR. Mil-
rinone for refractory cerebral vasospasm with delayed cerebral ischemia. J
ARTICLE INFORMATION Neurosurg. 2020;134:971–982. doi: 10.3171/2020.1.JNS193107
13. Senbokuya N, Kinouchi H, Kanemaru K, Ohashi Y, Fukamachi A, Yagi S,
Shimizu T, Furuya K, Uchida M, Takeuchi N, et al. Effects of cilostazol on
Affiliation cerebral vasospasm after aneurysmal subarachnoid hemorrhage: a multi-
Division of Neurocritical Care, Department of Neurology and Neurosurgery, center prospective, randomized, open-label blinded end point trial. J Neuro-
Emory University School of Medicine, Atlanta, GA. surg. 2013;118:121–130. doi: 10.3171/2012.9.JNS12492
14. Sadan O, Waddel H, Moore R, Feng C, Mei Y, Pearce D, Kraft J, Pimentel
Disclosures C, Mathew S, Akbik F, et al. Does intrathecal nicardipine for cerebral vaso-
None. spasm following subarachnoid hemorrhage correlate with reduced delayed
cerebral ischemia? A retrospective propensity score-based analysis. J Neu-
rosurg. 2022;136:115–124. doi: 10.3171/2020.12.JNS203673
15. Weiss M, Conzen C, Mueller M, Wiesmann M, Clusmann H, Albanna W,
REFERENCES Schubert GA. Endovascular rescue treatment for delayed cerebral isch-
1. Pegoli M, Mandrekar J, Rabinstein AA, Lanzino G. Predictors of excellent emia after subarachnoid hemorrhage is safe and effective. Front Neurol.
Downloaded from http://ahajournals.org by on December 25, 2023

functional outcome in aneurysmal subarachnoid hemorrhage. J Neurosurg. 2019;10:136. doi: 10.3389/fneur.2019.00136

2015;122:414–418. doi: 10.3171/2014.10.JNS14290 16. Lim J, Cho YD, Kwon HJ, Byoun SH, Koh HS, Park B, Choi SW. Dura-
2. Luong CQ, Ngo HM, Hoang HB, Pham DT, Nguyen TA, Tran TA, Nguyen tion of vasodilatory action after intra-arterial infusions of calcium chan-
DN, Do SN, Nguyen MH, Vu HD, et al. Clinical characteristics and factors nel blockers in animal model of cerebral vasospasm. Neurocrit Care.
relating to poor outcome in patients with aneurysmal subarachnoid hem- 2021;34:867–875. doi: 10.1007/s12028-020-01112-0
orrhage in vietnam: a multicenter prospective cohort study. PLoS One. 17. Kramer A, Selbach M, Kerz T, Neulen A, Brockmann MA, Ringel F,
2021;16:e0256150. doi: 10.1371/journal.pone.0256150 Brockmann C. Continuous intraarterial nimodipine infusion for the treatment
3. Allen GS, Ahn HS, Preziosi TJ, Battye R, Boone SC, Boone SC, Chou SN, of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage: a
Kelly DL, Weir BK, Crabbe RA, et al. Cerebral arterial spasm–a controlled retrospective, single-center cohort trial. Front Neurol. 2022;13:829938. doi:
trial of nimodipine in patients with subarachnoid hemorrhage. N Engl J Med. 10.3389/fneur.2022.829938
1983;308:619–624. doi: 10.1056/NEJM198303173081103 18. Wiess M, Albanna W, Conzen-Dilger C, Kastenholz N, Seyfried K, Ridwan H,
4. Pickard JD, Murray GD, Illingworth R, Shaw MD, Teasdale GM, Foy PM, Wiesmann M, Veldeman M, Schmidt TP, Megjhani M, et al.
Humphrey PR, Lang DA, Nelson R, Richards P. Effect of oral nimodip- Intraarterial nimodipine versus induced hypertension for delayed
ine on cerebral infarction and outcome after subarachnoid haemor- cerebral ischemia: a modified treatment protocol. Stroke.
rhage: british aneurysm nimodipine trial. BMJ. 1989;298:636–642. doi: 2022;53:2607–2616. doi: 10.1161/STROKEAHA.121.038216
10.1136/bmj.298.6674.636 19. Kapapa T, König R, Mayer B, Braun M, Schmitz B, Müller S, Schick J, Wirtz
5. Maher M, Schweizer TA, Macdonald RL. Treatment of spontaneous sub- CR, Pala A. Adverse events and complications in continuous intra-arterial
arachnoid hemorrhage: guidelines and gaps. Stroke. 2020;51:1326–1332. nimodipine infusion therapy after aneurysmal subarachnoid hemorrhage.
doi: 10.1161/STROKEAHA.119.025997 Front Neurol. 2021;12:812898. doi: 10.3389/fneur.2021.812898

Stroke. 2022;53:2617–2619. DOI: 10.1161/STROKEAHA.122.039800 August 2022   2619