Neuroimaging-Based Responses to Blood Pressure Augmentation in Acute Ischaemic Stroke: A Systematic Review

Abstract

Introduction

In acute ischaemic stroke, the key treatment to reduce infarct growth is reperfusion, achieved through thrombolysis, endovascular thrombectomy, or endogenous reperfusion. Prior to definitive reperfusion therapy, blood pressure augmentation may enhance cerebral perfusion and reduce interim infarct growth. This study aimed to summarise the existing evidence from randomised controlled trials on the use of imaging for patient selection and the assessment of blood pressure augmentation in acute ischaemic stroke.

Methods

A systematic review was conducted of the databases PubMed, Embase, and Cochrane Library in accordance with the PRISMA guidelines. The systematic review was prospectively registered on PROSPERO.

Results

Initial searches returned 266 results, of which 4 fulfilled inclusion criteria. Most identified studies did not utilise imaging for patient selection and the assessment of blood pressure augmentation in ischaemic stroke. Only two studies utilised magnetic resonance imaging and/or magnetic resonance perfusion imaging for patient selection, while one study used non-contrast CT brain. No studies utilised CT perfusion imaging for patient selection or outcome assessment post-blood pressure augmentation. There is also a lack of evidence regarding the association between specific perfusion imaging parameters, such as cerebral blood volume and delay time, and clinical outcomes post-blood pressure augmentation.

Conclusion

Imaging is a potentially valuable surrogate marker of cerebral perfusion, yet it has not been routinely used for patient selection and assessment in blood pressure augmentation in acute ischaemic stroke trials. Additional research is required to determine its utility in assessing the efficacy of blood pressure augmentation in ischaemic stroke.

Introduction

In acute ischaemic stroke (AIS), infarction occurs rapidly in areas of severely reduced blood flow, and progressively in areas of less severe hypoperfusion [1]. The key treatment to reduce infarct growth is by reperfusion, by either thrombolysis, endovascular thrombectomy or endogenous reperfusion [2, 3]. Blood pressure augmentation may improve cerebral perfusion to reduce infarct growth until either spontaneous or interventional-based reperfusion occurs.

As with other aspects of hyperacute ischaemic stroke intervention, patient selection, including the use of advanced imaging strategies, will likely be vital to intervention success. Previous systematic reviews have been conducted on clinical responses to blood pressure augmentation strategies in this setting [4, 5]. These reviews determined that previous studies were inconclusive. However, these reviews provided relatively scant detail on patient selection criteria for pressor support. There was also limited detail on imaging strategies for patient selection and assessment of treatment responsiveness. In recent years, various imaging techniques such as computed tomography (CT), magnetic resonance imaging (MRI), and perfusion imaging have become widely available and routinely used in hyperacute ischaemic stroke management [6–9]. The aims of this study were to summarise the existing evidence from randomised controlled trials, for [1] imaging in the selection of patients for blood pressure augmentation prior to acute reperfusion therapy in ischaemic stroke [2], multimodal stroke imaging responses to blood pressure augmentation for ischaemic stroke, and [3] the association between imaging and clinical outcomes following blood pressure augmentation in ischaemic stroke.

Materials and Methods

Study Design, Search Strategy, and Selection Criteria

The development and reporting of this systematic review were in accordance with the PRISMA guidelines (see checklist in online suppl. Information 1; for all online suppl. material, see https://doi.org/10.1159/000543341) [10]. Prospective registration with the PROSPERO registry was completed (CRD42023429215). The databases PubMed, Cochrane Library, and Embase were searched from inception to 19 June 2023. The search employed was based upon the following terms: (ischaemic stroke) AND (augmentation OR pressor OR induced blood pressure OR induced hypertension OR blood pressure manipulation) AND (CT or computed tomography OR MR OR magnetic resonance imaging OR MR perfusion). Online supplementary Information 2 provides the search strings employed for the respective databases. The reference lists of included articles were searched for relevant studies, and studies that subsequently have cited the included articles were also reviewed for relevant studies.

Studies were evaluated by two independent reviewers to determine whether inclusion criteria were met. This evaluation was conducted first based on titles and abstracts, prior to full-text review, using a standardised form. The inclusion criteria applied were as follows [1]: primary research study with a randomised controlled trial study design (abstracts, posters, reviews, and editorials were excluded) [2]; included human patients with AIS [3]; evaluated pharmacological blood pressure augmentation during the period of ischaemic stroke; and [4] available in full text. Studies not published in English were not included. Instances of disagreement with respect to eligibility were resolved through discussion or consultation with a third reviewer.

Data Extraction and Analysis

Data extraction was performed by two reviewers using a standardised form. Data of interest included study characteristics (year, location, study design), patient factors (age, gender, premorbid modified Rankin scale, key comorbidities), stroke characteristics (location, aetiology, NIHSS on presentation), blood pressure augmentation strategy (agent, duration, blood pressure target), and imaging characteristics (imaging modality, change detected, association with clinical outcome). The Joanna Briggs Institute Critical Appraisal Checklist randomised controlled trials were used for risk of bias analysis [11]. This risk of bias analysis was performed separately by both reviewers.

Results

Search Results and Study Characteristics

The search strategy provided 271 results (see Fig. 1). Following the screening of titles/abstracts, there were 7 studies that underwent full-text review. Four randomised controlled trials met inclusion criteria (see Table 1). Risk of bias analysis of the included studies showed that they were of moderate-low risk of bias (see online suppl. Information 3).

Fig. 1.

Study selection.

Table 1.

Study characteristics

Reference; country	Patient factors			Imaging-related factors in study	Pressor agent used for blood pressure augmentation	Clinical and radiological outcomes post-blood pressure augmentation
General information	Patients in study Age Gender	Comorbidities	NIHSS at presentation (control arm; interventional arm[s])	(a) Imaging modality for diagnosis (b) Location (arterial territory) or aetiology of stroke (c) Imaging modality used to assess effect of blood pressure augmentation	(a) Pressor agent used (b) Blood pressure pre-augmentation in mm Hg (control group, intervention group) (c) Blood pressure target (d) Blood pressure post-augmentation in mm Hg (control group, intervention group)	(a) Change in MRI DWI or perfusion lesion volume (b) sICH post-blood pressure augmentation (c) NIHSS post-blood pressure augmentation (d) mRS <3 at 3 months post-stroke
Bang et al. [12] (2019)	153	Hypertension, hyperlipidaemia, diabetes, smoking history, alcohol abuse, atrial fibrillation, and previous ischaemic stroke	5.6; 7.6	(a) MRI DWI and PWI (b) Large artery atherosclerosis in 92, small vessel disease in 61 (c) MRI and MR perfusion on day 7 post-recruitment	(a) Phenylephrine (b) 146.5 (±16.8), 144.2 (±18.5) mm Hg; (c) Systolic blood pressure of 178.8 ±18.7 mm Hg	(a) Not specified (b) 0 in control group, 5/76 in intervention group (c) A favourable shift in the distribution of NIHSS score was found in the intervention group (unadjusted common odds ratio 2.17, 95% CI: 1.19–3.92, p = 0.011) (d) 63.2% in control group, 75% in intervention group
	$\overline{\mathrm{x}}$ 66.3
South Korea	F (51) M (102)
Hillis et al. [13] (2003)	15	Not specified	10.2; 13.8	(a) MRI with DWI and PWI (b) 13/15 anterior circulation stroke, 2/15 posterior circulation stroke; only ischaemic stroke from large artery atherosclerosis included (c) MRI with DWI and PWI on day 3 post-stroke	(a) Phenylephrine (b) MAP 94±15, 115±16 (c) Aimed for MAP increase 10–20% over 1–8 h with regular monitoring for motor/cognitive improvement; in the absence of improvement, the target MAP was increased by 10% increments to MAP 130–140 for up to 12 h post-stroke	(a) Statistically non-significant increase in DWI volume of infarct from 22.4 mL (±37) to 24.3 mL (±3) in intervention group (b) No patients in intervention group developed haemorrhagic transformation, 1/6 in control group had asymptomatic haemorrhagic transformation on day 3 MR head (c) Mean day 3 NIHSS of 5.6 in intervention group and 12.3 in control group (p = 0.01) (d) Not assessed
	$\overline{\mathrm{x}}$ 63.5
America	F (11) M (4)
Deng et al. [14] (2019)	51	Hypertension, hyperlipidaemia, diabetes, smoking history, atrial fibrillation, ischaemic heart disease, and previous ischaemic stroke	13; 15	(a) Not specified (b) 7 ICA occlusions, 35 M1 occlusions, 18 M2 occlusions (c) Not specified	(a) Metaraminol (b) Not specified (c) Systolic blood pressure of 160–180 mm Hg (d) 139 (135–143), 167 (150–175)	(a) Not assessed (b) 1/26 in control group, 0/25 in intervention group (p = 1.00) (c) Early neurological improvement, defined as a reduction of NIHSS score of >8 from baseline or a score of 0/1 at 24 h occurred in 17/26 (65%) in control group, and 14/25 (56%) in intervention group (p = 0.57) (d) 16/62 (62%) in control group, 14/25 (56%) in intervention group (p = 0.779)
	$\overline{\mathrm{x}}$ 66.5
New Zealand	F (15) M (36)
Nasi et al. [15] (2019)	218	Hypertension, hyperlipidaemia, diabetes, smoking history, alcohol abuse, atrial fibrillation, and previous ischaemic stroke	7 (3–16), 8 (4–16), 8 (3–16)	(a) Non-contrast CT head (b) 195 anterior circulations, 44 cardiac embolisms, 51 large vessel atherothrombotic, 43 lacunars, 4 others, 76 undetermined (c) Non-contrast CT head (non-standardised timing of repeat scan)	(a) 500–1000 mL of bolus intravenous saline, IV noradrenaline (b) 166 (144–185) in 140–160 mm Hg group, 163 (140–189) in 161–180 mm Hg group, 169 (151–203) in 181–200 mm Hg group (c) Targeted systolic blood pressure of 140–160, 161–180, and 181–200 respectively	(a) Not assessed (b) 1/77 (1%) in 140–160 mm Hg group, 2/75 (3%) in 161–180 mm Hg group, 6/66 (9%) in 181–200 mm Hg group (c) Not specified (d) 39/77 (51%) in 140–160 Hg group, 39/75 (52%) in 161–180 mm Hg group, 26/66 (39%) in 181–200 mm Hg group
	$\overline{\mathrm{x}}$ 68.0
Brazil	F (101) M (117)

mRS, modified Rankin scale; sICH, symptomatic intracranial haemorrhage; MAP, mean arterial pressure.

Utilisation of Imaging in Patient Selection for Blood Pressure Augmentation

There were three studies that described using imaging in the selection of patients for blood pressure augmentation. These studies used MRI in two instances and non-contrast CT in one instance. The nature of the MRI findings that were used in these studies for patient selection varied. In particular, Bang et al. [12] included individuals with diffusion-weighted imaging (DWI) MRI performed within 24 h of symptom onset but did not specify any lesion volume required for trial inclusion [12]. On the other hand, Hillis et al. [13] only included individuals with more than 20% diffusion-perfusion mismatch volume on MRI. Deng et al. [14] made reference to the use of imaging with limited details about the imaging modality or parameters assessed. The study described the angiographic location of vessel occlusion and briefly discussed the possible use of CT angiography, but did not specify the imaging modality used.

Imaging Parameters in the Monitoring of Blood Pressure Augmentation Effects

Of the three studies that described the use of imaging in patient selection, only one study utilised imaging to monitor the effects of blood pressure augmentation. Hillis et al. [13] compared serial MRI DWI lesion volumes on day 0 and 3 post-stroke to assess the effect of blood pressure augmentation with phenylephrine. Bang et al. [12] used MRI prior to blood pressure augmentation but no repeat imaging was performed to evaluation for cerebrovascular haemodynamic changes post-blood pressure augmentation. Similarly, Nasi et al. [15] used non-contrast CT brain to select individuals for blood pressure augmentation but did not repeat the evaluation following the instigation of this potential therapy. None of the other included studies performed imaging for this role.

Stroke Outcome Evaluation with Advanced Imaging

In all of the included studies, clinical outcomes such as changes in National Institutes of Health Stroke Scale and modified Rankin Scale at 3 months were evaluated. However, no studies performed follow-up imaging analysis to determine the potential effects of blood pressure augmentation. Follow-up imaging was discussed in three studies, but the timing and modality of imaging used varied between the studies [12, 13, 15].

Three of the included studies used either MRI or CT to assess for symptomatic intracranial haemorrhage post-blood pressure augmentation. However, Deng et al. [14] did not specify the imaging modality used. None of the studies utilised classification systems for symptomatic intracranial haemorrhage (such as the Heidelberg classification system) [16].

Discussion

The included studies examining the potential utility of blood pressure augmentation in AIS have reported equivocal patient outcomes. However, the utilisation of advanced hyperacute stroke imaging to guide aspects of cerebral perfusion evaluation has been limited and may have resulted in suboptimal patient selection. Therefore, further research in this area is warranted.

MR and CT perfusion imaging are validated for assessment of cerebral perfusion in AIS [17–20]. Despite this, only one of the included studies utilised perfusion imaging for patient selection or evaluation of the effects of blood pressure augmentation therapies. This lack of use may be due to system factors such as the lack of availability of CT or MR perfusion imaging or difficulty in sourcing appropriately trained and qualified experts for perfusion imaging interpretation. In recent years, multimodal CT perfusion imaging has been widely utilised globally, especially in high-income countries [21]. Future studies should aim to utilise CT or MR perfusion imaging which may improve patient selection and outcome evaluation.

CT perfusion imaging and non-contrast CT brain are suboptimal imaging modalities for diagnosing acute posterior circulation ischaemic stroke [22]. MRI has higher diagnostic sensitivity for posterior circulation stroke and should be routinely utilised in trials evaluating blood pressure augmentation therapies in these patients [23]. The improving availability of automated MR analysis software such as RAPID and MIStar would allow future studies to compare serial software-analysed lesion volumes to determine the effect of blood pressure augmentation therapies on cerebral perfusion [24]. Software-based automated analysis of stroke lesion volumes may improve the reliability and generalisability of future studies [25, 26].

Limitations

This systematic review has several limitations that should be acknowledged. The exclusion of non-English language publications may have limited the findings of the review. Additionally, particularly in an area with multiple negative studies, publication bias may influence the results of the systematic review.

Conclusion

The majority of existing randomised clinical trials of blood pressure augmentation in ischaemic stroke has not used modern hyperacute stroke imaging in patient selection. Accordingly, patient selection in these trials may have been suboptimal. Future research evaluating blood pressure augmentation in AIS should aim to regularly utilise advanced stroke imaging modalities, such as multimodal CT or MR perfusion imaging for patient selection and outcome assessment. These easily available and validated imaging modalities may improve the evaluation of blood pressure augmentation therapies in AIS.

Statement of Ethics

A statement of ethics is not applicable because this study is based exclusively on published literature.

Conflict of Interest Statement

The authors declare that there is no conflict of interest.

Funding Sources

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Author Contributions

R.G.: conceptualisation, formal analysis, investigation, methodology, and writing – original draft, review, and editing; S.E.-M., D.Z., and D.S.: investigation and writing – review and editing; F.N., S.B., J.J., and T.K.: writing – review and editing.

Funding Statement

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Data Availability Statement

All data generated or analysed during this study are included in this article and its supplementary material files. Further enquiries can be directed to the corresponding author.