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• W4281678767 abstract "HomeStrokeVol. 53, No. 8Treating Delayed Cerebral Ischemia: Should We Focus on Blood Pressure or Vasodilatation? Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBTreating Delayed Cerebral Ischemia: Should We Focus on Blood Pressure or Vasodilatation? Ofer Sadan, MD, PhD and Feras Akbik, MD, PhD Ofer SadanOfer Sadan 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 E-mail Address: [email protected] https://orcid.org/0000-0002-0050-3025 Division of Neurocritical Care, Department of Neurology and Neurosurgery, Emory University School of Medicine, Atlanta, GA. Search for more papers by this author and Feras AkbikFeras Akbik https://orcid.org/0000-0002-1255-1622 Division of Neurocritical Care, Department of Neurology and Neurosurgery, Emory University School of Medicine, Atlanta, GA. Search for more papers by this author Originally published8 Jun 2022https://doi.org/10.1161/STROKEAHA.122.039800Stroke. 2022;53:2617–2619This article is a commentary on the followingIntraarterial Nimodipine Versus Induced Hypertension for Delayed Cerebral Ischemia: A Modified Treatment ProtocolOther version(s) of this articleYou are viewing the most recent version of this article. Previous versions: June 8, 2022: Ahead of Print See related article, p 2607Delayed cerebral ischemia (DCI) following subarachnoid hemorrhage remains a significant clinical challenge. Its clinical importance stems from 2 distinct features: the significant correlation between DCI and patient outcomes and its delayed appearance which allows time for intervention.1,2 The only treatment shown to prevent DCI is oral nimodipine,3,4 and therefore, it is the only level I recommendation in current clinical guidelines.5,6DCI often occurs in the settings of cerebral vasospasm and is, therefore, thought to be largely driven by local hypoperfusion,7 although alternative mechanisms likely contribute.8 The vasospasm and hypoperfusion theory led to 2 different paths of therapy: improving perfusion by induced hypertension and alleviating vasospasm by inducing vasodilatation, 2 mechanisms which often counteract one another.Induced hypertension has long been a cornerstone of therapy for cerebral vasospasm and DCI, originally as part of the triple-H therapy (hypertension, hypervolemia, and hemodilution). While some radiological-based benefit was found,9 the triple-H therapy gradually lost its role due to lack of clinical effect on patient outcomes.8 The specific role of induced hypertension remains controversial. On the one hand, anecdotal reports and experience of transient improvement in clinical status exists, yet on the other there is no data to support its use in a continuous fashion.10From the vasodilatory standpoint, although oral nimodipine demonstrated efficacy as early as the 1980s, countless lines of inquiry since then have not led to novel therapies. In a recent systematic review, Qureshi et al11 showed that there was no positive phase 3 clinical trial addressing DCI since the nimodipine ones, although different interventions were tried to induce vasodilatation, for example by using different calcium channel blockers, endothelin receptor antagonists, magnesium, or by oxidative stress reduction.Even with oral nimodipine, DCI remains a common complication, and in lieu of other proven interventions, multiple centers developed off-label rescue treatments. For some, there is prospective controlled data to support it (such as intravenous milrinone12 or oral cilostazol13). In others, data remains retrospective to the most part (eg, intrathecal nicardipine14). Another common rescue intervention is the application of intraarterial vasodilators during angiography, and mechanical interventions such as balloon or stent assisted angioplasty.15 These interventions are limited by invasive nature, short effect, and procedural risk.16 A combined approached was previously described in which the microcatheter is left in one or more of the cerebral arteries, while vasodilators such as nimodipine, are infused intraarterially in a continuous fashion for multiple days.15,17In the current issue of Stroke, Weiss et al18 published a retrospective analysis of a pre/post change in their usual care protocol. In the original clinical protocol, all patients with clinical DCI or high-risk patients (for examples those with perfusion deficit on CT-perfusion, or a significant reduction in partial pressure of brain tissue oxygen—PtiO2) were treated with induced hypertension. Refractory cases were further treated with continuous intraarterial nimodipine using one or more microcatheters left in any of the carotid or vertebral arteries (IAN), while maintaining an elevated systolic blood pressure >180 mm Hg. Given the tension between induced hypertension and the hemodynamic effects of a continuous vasodilator therapy, the authors developed a novel protocol where the hemodynamic goal was reduced to systolic blood pressure >120 mm Hg for refractory cases receiving IAN, shifting the weight towards vasodilatation.Weiss et al,18 describe that although IAN was locally administered, it often resulted in hypotension, relative to the standard of care goal of systolic blood pressure >180 mm Hg, or absolute hypotension, related to the systemic vasodilatory effects of nimodipine. The reduced blood pressure, compared with the threshold set, required a high dose of vasoactive drips (mainly norepinephrine). The authors hypothesized that such high doses of norepinephrine may have negative systemic and cerebral results, which rationalized the change of the blood pressure goal to >120 mm Hg.The primary outcome of this study was to demonstrate reduction in norepinephrine use following the protocol change, along with overall safety of this regimen. The secondary outcomes were markers of perfusions (namely PtiO2), intracranial pressure, DCI-related infarcts and long-term functional outcomes of the patients.The study enrolled a total of 243 subarachnoid hemorrhage patients over 7 years in a single center. Forty-nine patients developed refractory vasospasm which did not respond to induced hypertension and deemed to require IAN. Of the 49 patients, 29 were treated with IAN along with induced hypertension (old protocol) and 20 with the new one without the induced hypertension. The 2 groups were similar from a demographic standpoint, as well as main risk factors, aneurysm location, and aneurysm obliteration approach (surgical versus endovascular).Unsurprisingly, norepinephrine doses were ≈60% lower with lower blood pressure goals. The authors further report a similar rate of the study’s defined serious complications (eg, new onset heart failure or renal failure, in about 20% overall), and a lower rate of minor complications in the alternative approach, specifically showing a decrease in the rate of peripheral hypoperfusion and arrythmias. However, the treatment was not tolerated by a similar proportion of patients (51.7% in the induced hypertension group versus 35% in the alternative group).For the secondary, efficacy outcomes, the authors used multimodal monitoring which allowed them to measure surrogates for cerebral perfusion. Interestingly, the ptiO2 was higher in the group with the lower blood pressure goal, as well as a lower average intracranial pressure. These 2 results could be contradictory to some degree. Induced hypertension with norepinephrine can cause cerebral vasoconstriction, and therefore, reduced perfusion; therefore, the anticipated result of vasoconstriction would be reduced PtiO2. However, if vasocontraction is driving the difference in ptiO2, intracranial pressure should be lower in the group treated with higher doses of norepinephrine due to a reduction in cerebral blood volume. The authors hypothesized that this discrepancy is related to altered autoregulation in the settings of an acute brain injury such as subarachnoid hemorrhage.It is worth considering that the vasoconstrictor effect of norepinephrine is dose dependent. This mixed effect could be the result of high norepinephrine dose on the one hand and causing vasoconstriction, while blunting the β-adrenergic effect on improved cardiac output. The combination of highly activated vasoconstricting α-1 adrenergic receptors with the vasodilatory calcium channel blocker likely results in an effect outside of normal physiological response. Regardless, prolonged induced hypertension in this report was associated with reduced perfusion both based on the intracranial pressure (which is a key component of the cerebral perfusion pressure) and tissue oxygen delivery.When assessing clinically relevant patient outcomes, no differences were demonstrated between the 2 protocols. Specifically, DCI-related infarction and long-term functional outcomes were similar. However, interpreting these outcomes is very limited by the small cohort in this report.Continuous IAN intervention is an aggressive and atypical type of rescue therapy. It certainly has advantages. For example, it reduced the need for repeated angiographies, and facilitated titration based on dose and location (placing the microcatheter in certain arteries). Yet, as the authors describe, this approach has many limitations as well. Maintaining IAN using microcatheters that dwell in the main cerebral arteries (carotids or vertebral) for days requires ongoing sedation, likely to a greater degree compared with patients who do not have microcatheters in place. It also required a continuous infusion of an antithrombotic agent (tirofiban in this report), which has its own risks, especially external ventricular drain-associated hemorrhages, postoperative bleeds, or spontaneous parenchymal hemorrhages (which were not reported herein). Indeed, in this cohort by Weiss et al, over 35% of subjects did not tolerate this intervention. Moreover, the catheters malfunctioned in over 20% of cases, and embolic event related to the microcatheter was documented in 8.1% of the cohort, which are objectively high rates of complications for any procedure. The thromboembolic complications occurred above and beyond DCI-related infarcts, the very complication that this intervention aims to prevent. The rate of complications will likely constrain widespread adoption in the absence of prospective studies.19 Moreover, the specific use of intraarterial nimodipine cannot be adopted in the United States, since its intravenous formation is not approved by the Food and Drug Administration.This study does deliver 2 important messages: first, the clear unmet need to develop effective and safe treatments for patients at high risk for DCI remains; and second, the data delivers indirect evidence to the lack of effect, and potential harm of continuous induced hypertension for patients with cerebral vasospasm-related DCI. In the on-going tension between the induced hypertension approach to address cerebral vasospasm induced hypoperfusion and induced vasodilatation, focusing on the local administration of a vasodilator seems to have a favorable effect. Although locally administered, the intraarterial approach suffered from a high complication rate and systemic adverse events. Further studies are needed to understand the changing physiology of these complicated patients, to select the appropriate treatment, for the appropriate patient, at the appropriate time.Article InformationDisclosures None.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Disclosures, see page 2619.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.[email protected]comReferences1. 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Wiess M, Albanna W, Conzen-Dilger C, Kastenholz N, Seyfried K, Ridwan H, Wiesmann M, Veldeman M, Schmidt TP, Megjhani M, et al. Intraarterial nimodipine versus induced hypertension for delayed cerebral ischemia: a modified treatment protocol.Stroke. 2022; 53:2607–2616. doi: 10.1161/STROKEAHA.121.038216Google Scholar19. Kapapa T, König R, Mayer B, Braun M, Schmitz B, Müller S, Schick J, Wirtz CR, Pala A. Adverse events and complications in continuous intra-arterial nimodipine infusion therapy after aneurysmal subarachnoid hemorrhage.Front Neurol. 2021; 12:812898. doi: 10.3389/fneur.2021.812898Google Scholar Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesIntraarterial Nimodipine Versus Induced Hypertension for Delayed Cerebral Ischemia: A Modified Treatment ProtocolMiriam Weiss, et al. Stroke. 2022;53:2607-2616 August 2022Vol 53, Issue 8 Advertisement Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/STROKEAHA.122.039800PMID: 35674047 Originally publishedJune 8, 2022 Keywordsoxygensubarachnoid hemorrhageperfusionEditorialsangiographyblood pressurebrain ischemiaPDF download Advertisement SubjectsCerebral AneurysmCerebrovascular Disease/StrokeTreatment" @default.
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