An updated systematic review and meta-analysis investigating perihematomal edema and clinical outcome after intracerebral hemorrhage

Marchina, Sarah; Lee, Kun He; Lioutas, Vasileios‐Arsenios; Carvalho, Filipa; Incontri‐Abraham, Diego; Heistand, Elizabeth; Lin, David; Selim, Magdy

doi:10.1016/j.jstrokecerebrovasdis.2023.107204

Cited by 3 publications

(4 citation statements)

References 41 publications

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“…Future studies should aim to identify if any biomarker is associated with both, since such a biomarker could either be a prognostic marker after ICH or act as an inflammatory mediator which would be more likely to be a potential therapeutic target. Since both animal studies and human studies (of brain tissue and serum) suggest the involvement of inflammatory pathways such as IL-1, HMGB-1, TNF in the perihaematomal region 133 and the development of PHO 126 , and PHO itself is associated with outcome after ICH 134 , 135 , it is plausible that one or more such biomarkers could be involved in the inflammatory response in the brain following ICH.’ Modulating the neuroinflammatory response after ICH, for example by using an IL-1 receptor antagonist (NCT04834388) may therefore hold promise.…”

Section: Discussionmentioning

confidence: 99%

“…None of the studies included in meta-analysis reported whether the biomarker helped to improve prediction of prognosis after ICH when compared or added to existing prognostic scores for ICH and this should be examined in future studies. We were unable to explore how variation in PHO measurement between studies affects any association between PHO and prognosis after ICH but this has been discussed elsewhere 134 , 135 .…”

Section: Discussionmentioning

confidence: 99%

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Association between circulating inflammatory biomarkers and functional outcome or perihaematomal oedema after ICH: a systematic review & meta-analysis

Kirby,

Barrington,

Sondag

et al. 2023

Wellcome Open Res

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Background Currently, there are no specific medical treatments for intracerebral haemorrhage (ICH), but the inflammatory response may provide a potential route to treatment. Given the known effects of acute brain injury on peripheral immunity, we hypothesised that inflammatory biomarkers in peripheral blood may be associated with clinical outcome following ICH, as well as perihaematomal oedema (PHO), which is an imaging marker of the neuroinflammatory response. Methods We searched OVID Medline and EMBASE on 07 April 2021 for studies of humans with ICH measuring an inflammatory biomarker in peripheral blood and PHO or clinical outcome. Risk of bias was assessed both by using a scale comprising features of the Newcastle-Ottawa Assessment Scale, STROBE-ME and REMARK guidelines, and for studies included in meta-analysis, also by the QUIPS tool.We used random effects meta-analysis to pool standardised mean differences (SMD) if ≥1 study quantified the association between identical biomarkers and measures of PHO or functional outcome. Results Of 8,615 publications, 16 examined associations between 21 inflammatory biomarkers and PHO (n=1,299 participants), and 93 studies examined associations between ≥1 biomarker and clinical outcome (n=17,702 participants). Overall, 20 studies of nine biomarkers (n=3,199) met criteria for meta-analysis of associations between inflammatory biomarkers and clinical outcome. Death or dependency (modified Rankin Scale (mRS) 3‒6) 90 days after ICH was associated with higher levels of fibrinogen (SMD 0.32; 95%CI [0.04, 0.61]; p=0.025), and high mobility group box protein 1 (HMGB1) (SMD 1.67; 95%CI [0.05, 3.30]; p=0.04). Higher WBC was associated with death or dependency at 90 days (pooled SMD 0.27; 95% CI [0.11, 0.44]; p=0.001; but the association was no longer significant when the analysis was restricted to studies with a low risk of bias (pooled SMD 0.22; 95% CI -0.04-0.48). Higher CRP seemed to be associated with death or dependency at 90 days (pooled SMD 0.80; 95% CI [0.44, 1.17]; p<0.0001) but this association was no longer significant when adjusted OR were pooled (OR 0.99 (95% CI 0.98-1.01)). Conclusions Higher circulating levels of, fibrinogen and HMGB1 are associated with poorer outcomes after ICH. This study highlights the clinical importance of the inflammatory response to ICH and identifies additional research needs in determining if these associations are mediated via PHO and are potential therapeutic targets. Registration PROSPERO (CRD42019132628; 28/05/2019).

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Association between circulating inflammatory biomarkers and functional outcome or perihaematomal oedema after ICH: a systematic review & meta-analysis

Kirby,

Barrington,

Sondag

et al. 2023

Wellcome Open Res

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“…Many animal studies indirectly support the beneficial effects of reducing edema on lowering ICP [6,11,27,28], but several animal and clinical studies do not [11,26,27,[29][30][31][32][33][34]. A recent meta-analysis investigated the impact of PHE on ICH outcomes and found a weak association between PHE and clinical outcome [33,35], with high heterogeneity noted among studies. The high heterogeneity may be due in part to differences in PHE measurement among studies, as various methods of assessing PHE outcome (e.g., absolute vs relative edema, edema volume vs edema growth) and timepoints (e.g., 24 hours post-ICH, 72 hours post-ICH) were used [33,35].…”

Section: Introductionmentioning

confidence: 99%

“…A recent meta-analysis investigated the impact of PHE on ICH outcomes and found a weak association between PHE and clinical outcome [ 33 , 35 ], with high heterogeneity noted among studies. The high heterogeneity may be due in part to differences in PHE measurement among studies, as various methods of assessing PHE outcome (e.g., absolute vs relative edema, edema volume vs edema growth) and timepoints (e.g., 24 hours post-ICH, 72 hours post-ICH) were used [ 33 , 35 ]. While pre-clinical studies are more methodologically homogenous and predominantly use biochemical (wet-weight dry-weight) methods to assess edema, differences among study quality, sample sizes, and similar factors may have a large effect on differences among relatively homogenous animal populations.…”

Section: Introductionmentioning

confidence: 99%

A systematic review and meta-analysis on the efficacy of glibenclamide in animal models of intracerebral hemorrhage

Kung,

Wilkinson,

Liddle

et al. 2023

PLoS ONE

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Intracerebral hemorrhage (ICH) is a devastating stroke with many mechanisms of injury. Edema worsens outcome and can lead to mortality after ICH. Glibenclamide (GLC), a sulfonylurea 1- transient receptor potential melastatin 4 (Sur1-Trpm4) channel blocker, has been shown to attenuate edema in ischemic stroke models, raising the possibility of benefit in ICH. This meta-analysis synthesizes current pre-clinical (rodent) literature regarding the efficacy of post-ICH GLC administration (vs. vehicle controls) on behaviour (i.e., neurological deficit, motor, and memory outcomes), edema, hematoma volume, and injury volume. Six studies (5 in rats and 1 in mice) were included in our meta-analysis (PROSPERO registration = CRD42021283614). GLC significantly improved behaviour (standardized mean difference (SMD) = −0.63, [−1.16, −0.09], n = 70–74) and reduced edema (SMD = −0.91, [−1.64, −0.18], n = 70), but did not affect hematoma volume (SMD = 0.0788, [−0.5631, 0.7207], n = 18–20), or injury volume (SMD = 0.2892, [−0.4950, 1.0734], n = 24). However, these results should be interpreted cautiously. Findings were conflicted with 2 negative and 4 positive reports, and Egger regressions indicated missing negative edema data (p = 0.0001), and possible missing negative behavioural data (p = 0.0766). Experimental quality assessed via the SYRCLE and CAMARADES checklists was concerning, as most studies demonstrated high risks of bias. Studies were generally low-powered (e.g., average n = 14.4 for behaviour), and future studies should employ sample sizes of 41 to detect our observed effect size in behaviour and 33 to detect our observed effect in edema. Overall, missing negative studies, low study quality, high risk of bias, and incomplete attention to key recommendations (e.g., investigating female, aged, and co-morbid animals) suggest that further high-powered confirmatory studies are needed before conclusive statements about GLC’s efficacy in ICH can be made, and before further clinical trials are performed.

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Perihaematomal Oedema Evolution over 2 Weeks after Spontaneous Intracerebral Haemorrhage and Association with Outcome: A Prospective Cohort Study

Samarasekera,

Ferguson,

Parry-Jones

et al. 2024

Cerebrovasc Dis

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Introduction We know little about the evolution of perihaematomal oedema (PHO) >24 hours after ICH onset. We aimed to determine the trajectory of PHO after ICH onset and its association with outcome. Methods We did a prospective cohort study using a pre-specified scanning protocol in adults with first-ever spontaneous ICH and measured absolute PHO volumes on CT head scans at ICH diagnosis and 3±2, 7±2 and 14±2 days after ICH onset. We used the largest ICH if ICHs were multiple. The primary outcomes were (a) the trajectory of PHO after ICH onset and (b) the association between PHO (absolute volume at the time when most repeat CT head scans were obtained, and change in PHO volume at this time compared with the first CT head scan) and poor functional outcome (modified Rankin scale 3-6 at 90 days). We pre-specified multivariable logistic regression models of this association adjusting analyses for potential confounders: age, GCS, infratentorial ICH location and intraventricular extension. Results In 106 participants of whom forty nine (46%) were female, with a median ICH volume 7ml (interquartile range [IQR] 2-22ml), the trajectory of median PHO volume was an increase from 14ml (IQR 7-26ml) at diagnosis to 18ml (IQR 8-40ml) at 3±2 days (n=87), 20ml (IQR 8-48ml) at 7±2 days (n=93) and 21ml (IQR 10-54ml) at 14±2 days (n=78) (p=<0.001). PHO volume at each time point was collinear with ICH volume at diagnosis (│r│>0.7) but the change in PHO volume between diagnosis and each time point was not. Given collinearity, we used total lesion (i.e. ICH+PHO) volume instead of PHO volume in a logistic regression model of its association at each time point with outcome. Increasing total lesion (ICH+PHO) volume at day 7±2 was associated with poor functional outcome (adjusted OR per ml 1.02, 95% CI 1.00-1.03; p=0.036) but the increase in PHO volume between diagnosis and day 7±2 was not associated with poor functional outcome (adjusted OR per ml 1.03, 95% CI 0.99-1.07; p=0.132). Conclusion PHO volume increases throughout the first two weeks after onset of mild to moderate ICH. Total lesion (ICH+PHO) volume at day 7±2 was associated with poor functional outcome but the change in PHO volume between diagnosis and day 7±2 was not. Prospective cohort studies with larger sample sizes are needed to investigate these associations and their modifiers.

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An updated systematic review and meta-analysis investigating perihematomal edema and clinical outcome after intracerebral hemorrhage

Cited by 3 publications

References 41 publications

Association between circulating inflammatory biomarkers and functional outcome or perihaematomal oedema after ICH: a systematic review & meta-analysis

Association between circulating inflammatory biomarkers and functional outcome or perihaematomal oedema after ICH: a systematic review & meta-analysis

A systematic review and meta-analysis on the efficacy of glibenclamide in animal models of intracerebral hemorrhage

Perihaematomal Oedema Evolution over 2 Weeks after Spontaneous Intracerebral Haemorrhage and Association with Outcome: A Prospective Cohort Study

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