Effect of Early Brain Infarction After Subarachnoid Hemorrhage: A Systematic Review and Meta-Analysis

doi:10.1016/j.wneu.2018.04.037

World Neurosurgery

Volume 115, July 2018, Pages e292-e298

https://doi.org/10.1016/j.wneu.2018.04.037 Get rights and content

Highlights

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Early brain infarction in aneurysmal subarachnoid hemorrhage refers to the injury within the first 72 hours.
•
The incidence of early brain infarction was of 17%.
•
Early brain infarction plays an important role in the outcome of patients with subarachnoid hemorrhage.
•
Early brain infarction has a negative impact in mortality and functional outcome.
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May represent a new therapeutic frontier for preventing poor outcomes.

Objective

Aneurysmal subarachnoid hemorrhage (aSAH) is an acute cerebrovascular event that leads to devastating consequences. Early brain infarction (EBI) develops very early, within the first 72 hours after bleeding, and may have a significant impact on long-term outcomes. The incidence and impact of EBI in the prognosis of aSAH remain uncertain. We performed a systematic review and meta-analysis to evaluate the incidence of EBI in patients with aSAH and determine its effect on mortality and functional outcomes.

Methods

We performed a systematic review and meta-analysis. Inclusion criteria were 1) studies that evaluated aSAH within 72 hours after bleeding; 2) performed a brain imaging study up to 72 hours of hemorrhage; 3) used computed tomography or magnetic resonance imaging; and 4) included a description of the findings of the brain imaging study (whether or not an infarct was present).

Results

Ten studies that met the criteria were included. The incidence of EBI was 17%. The risk ratio for 3-month mortality was 2.18 (95% confidence interval 1.48–3.30). The overall risk ratio for poor outcome was 2.26 (95% confidence interval 1.75–2.93).

Conclusions

EBI plays an important role in the outcome of patients with aSAH. Its significant impact could represent a new therapeutic frontier for improving outcomes of these patients.

Introduction

Aneurysmal subarachnoid hemorrhage (SAH) is an acute cerebrovascular event that leads to devastating consequences. The mortality due to aneurismal SAH is high, and survivors may develop major neurological disabilities.1, 2

Mortality from SAH can be as high as 15% before hospital admission and may reach 40%–45% 30 days after bleeding. The incidence of aneurysmal SAH ranges from 6/100,000 to 11/100,000 people per year and accounts for 5% of all strokes. Approximately 70% of all people with aneurysmal SAH will either die or require help with daily activities at 6 months after the initial injury.1, 2

Delayed cerebral ischemia (DCI) has been described as the most important factor associated with poor functional outcome and mortality in patients who survive the initial hemorrhage, albeit preventable.² Although vasospasm is considered the main known cause of DCI, other mechanisms may play a role, such as microembolism, microthrombi, and cortical spreading depression.2, 3, 4 However, DCI is not the only determinant of the outcome. Recently, early brain injury has emerged as a potential risk factor for poor outcome. Its nature is still poorly understood; however, it seems to be a composite of ischemia, edema, and poor cerebral perfusion.

The term early brain injury has only recently been described, and it refers to a brain injury that develops within the first 72 hours after the ictus.⁵ Therefore, it refers to the events that occur in the brain before the development of delayed ischemia, and it probably has an alternative pathophysiology. At present, early brain injury is being extensively studied, and its mechanisms are only beginning to be understood. It appears that early brain injury occurs as a combination of physiologic insults to the brain, which results in global ischemia, blood-brain barrier breakdown, edema, and cellular death signaling.⁶

In animal models, studies have shown that the early hemodynamic changes and severe intracranial hypertension associated with reduced cerebral perfusion pressure are present early after bleeding. Thus, ischemia may develop soon after aneurysmal SAH and lead to early brain injury.⁷

Regardless of the mechanism, cerebral infarction is the final manifestation of multiple pathways of neuronal lesion and could therefore account for the many mechanisms of initial brain injury.

Although this neuronal injury develops very early in the course of the disease, it may have a significant impact on long-term outcomes. The incidence and impact of early brain infarction (EBI) in the prognosis of patients with aneurysmal SAH remains uncertain. Therefore, we performed a systematic review and meta-analysis to evaluate the incidence of EBI in patients with aneurysmal SAH (as it is an objective measure of the initial injury) and to determine the effect of EBI on SAH mortality and functional outcomes.

Section snippets

Search Strategy and Selection Criteria

We carried out a systematic review and meta-analysis of articles using the methodology recommended by the Cochrane Collaboration,⁸ and we prepared this study according to the PRISMA statement.⁹ Two investigators (B.G. and N.M.) independently conducted a systematic electronic search on PubMed up to December 2015. There was no language restriction. The following terms were used:

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early (all fields) AND “brain injuries” (MeSH terms) AND hemorrhage, subarachnoid (MeSH terms)
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early brain injury

Results

The first search resulted in 4004 studies. After duplicates were excluded and relevant abstracts were found, 33 articles were selected for full text evaluation. Among these articles, 23 were excluded (7 had brain imaging without descriptions of the infarctions, 7 were review articles, 1 was a case report, 4 had brain imaging studies after 72 hours of bleeding, 1 studied a different pathology, and 2 did not have any brain imaging studies). Among the excluded studies, 1 study¹² did fit the

Discussion

A rather large incidence of EBI was detected in the meta-analysis (17%), especially when MRI is used as a method of diagnosis (41%). A higher incidence of EBI was expected in MRI studies as MRI has both a higher sensitivity and specificity for the detection of infarction than a CT scan, and it can provide earlier detection.²³ However, studies with early MRI are more limited in number.

The meta-analysis results also show a significant association between EBI and increased mortality and poor

Conclusion

In summary, based on the results of the present meta-analysis, EBI, which reflects an early injury to the brain after the initial bleeding, plays an important role in the outcome of patients with SAH and has a significant impact on mortality and morbidity. This finding could represent a new therapeutic frontier for improving outcomes in these patients with such a devastating disease.

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Advances in biomarkers for vasospasm – Towards a future blood-based diagnostic test
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Cerebral vasospasm and the resultant delayed cerebral infarction is a significant source of mortality following aneurysmal SAH. Vasospasm is currently detected using invasive or expensive imaging at regular intervals in patients following SAH, thus posing a risk of complications following the procedure and financial burden on these patients. Currently, there is no blood-based test to detect vasospasm.
PubMed, Web of Science, and Embase databases were systematically searched to retrieve studies related to cerebral vasospasm, aneurysm rupture, and biomarkers. The study search dated from 1997 to 2022. Data from eligible studies was extracted and then summarized.
Out of the 632 citations screened, only 217 abstracts were selected for further review. Out of those, only 59 full text articles met eligibility and another 13 were excluded.
We summarize the current literature on the mechanism of cerebral vasospasm and delayed cerebral ischemia, specifically studies relating to inflammation, and provide a rationale and commentary on a hypothetical future bloodbased test to detect vasospasm. Efforts should be focused on clinical-translational approaches to create such a test to improve treatment timing and prediction of vasospasm to reduce the incidence of delayed cerebral infarction.
Early Cerebral Infarction After Aneurysmal Subarachnoid Hemorrhage Is Associated with Prior Global Cerebral Hypoperfusion
2022, World Neurosurgery
Citation Excerpt :
Others studies reporting a higher rate of ECI included iatrogenic infarction24,25 or selected poor-grade patients with a higher risk of ECI.26,27 Our study also confirms that ECI mostly occurs in poor-grade aSAH22,26,28,29 and is associated with poor outcomes, independent of grade at presentation.22-26,28-30 The association between impaired global cerebral perfusion and cerebral ischemia is well established after cardiac arrest or states of shock.16
Early cerebral infarction (ECI) is an independent factor associated with poor outcome following aneurysmal subarachnoid hemorrhage (aSAH). We aimed to test the association between ECI and prior global impairment of cerebral perfusion.
We performed a retrospective cohort study of consecutive patients admitted for aSAH in 2 centers. ECI was defined as any radiological cerebral infarction identified within 3 days from the onset of bleeding and not related to aneurysm repair. Global impairment of cerebral perfusion was defined as clinical or transcranial Doppler signs of brain hypoperfusion together with circulatory failure or intracranial hypertension in keeping with guidelines. The association between ECI and prior occurrence of global impairment of cerebral perfusion was tested using binary logistic regression adjusted for confounders identified in the univariate analysis.
Seven hundred fifty-three patients with aSAH were included. ECI was observed in 40 patients (5.3%; 95% CI = 3.7%–6.9%). Prior global impairment of cerebral perfusion occurred in 90% of them (60% in-hospital) versus in 11% of patients without ECI (P < 0.001). In the multivariate analysis, World Federation of Neurological Surgeons grade (OR = 2.3, 95% CI = 1.5–3.6, P<0.001), global impairment of cerebral perfusion due to circulatory failure (OR = 4.7, 95% CI = 1.8–11, P = 0.001), or intracranial hypertension (OR = 11.1, 95% CI = 3.8–32.3, P<0.001) was an independent risk factor for ECI.
Our study demonstrated that ECI is strongly associated with the prior occurrence of global impairment of cerebral perfusion, independent of World Federation of Neurological Surgeons grade. These patients may benefit from more intensive and systematic prevention of impaired cerebral perfusion, particularly in poor-grade patients.
The role of immune inflammation in aneurysmal subarachnoid hemorrhage
2021, Experimental Neurology
Citation Excerpt :
Therefore, the role of EBI in aSAH has gradually received attention. A systematic review and meta-analysis suggested a significant association between EBI and poor outcome and increased mortality (Goncalves et al., 2018). In addition, some pathological mechanisms that cause EBI, such as inflammation and oxidative stress, may contribute to promoting subsequent DCI (Rowland et al., 2012).
Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating disease, which mainly caused by the rupture of an intracranial aneurysm. Clinical trials have demonstrated that cerebral vasospasm (CVS) is not the sole contributor to delayed cerebral ischemia (DCI) and poor outcomes in patients with aSAH. Currently, accumulating evidence suggests that early brain injury (EBI), which occurs within 72 h after the onset of aSAH, lays the foundation for subsequent pathophysiological changes and poor outcomes of patients. The pathological mechanisms of EBI mainly include increased intracranial pressure, oxidative stress, neuroinflammation, blood-brain barrier (BBB) disruption, cerebral edema and cell death. Among them, the brain immune inflammatory responses involve a variety of immune cells and active substances, which play an important role in EBI after aSAH and may be related to DCI and long-term outcomes. Thus, attention should be paid to strategies targeting cerebral immune inflammatory responses. In this review, we discuss the role of immune inflammatory responses in the occurrence and development of aSAH, as well as some inflammatory biomarkers related to CVS, DCI, and aSAH outcomes. In addition, we also summarize the potential therapeutic drugs that target cerebral immune inflammatory responses for patients with aSAH in current research.
The Impact of Extracerebral Infection After Subarachnoid Hemorrhage: A Single-Center Cohort Study
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Citation Excerpt :
Subarachnoid hemorrhage (SAH) is a devastating acute neurologic disease that affects many people worldwide,1 leading to severe disabilities and death.2 Poor neurologic outcome is related to secondary brain injury, including early hypoperfusion, neuroinflammation, and delayed cerebral ischemia (DCI).3-6 Nevertheless, additional systemic complications (e.g., fever, hypotension, anemia, hyperglycemia, and hyponatremia) can also deteriorate brain function and contribute to poor neurologic recovery.7
Subarachnoid hemorrhage (SAH) is associated with high morbidity. Among all complications, infections, in particular if hospital acquired, could represent an important cause of death in patients with SAH. The aim of this study was to describe infectious complications in patients with SAH and to evaluate their impact on outcome.
A single-center cohort study included all patients with SAH admitted from January 2011 to December 2016, who stayed in the intensive care unit for at least 24 hours. Infection diagnosis was retrieved from medical files; central nervous system infections were not included. A multivariable analysis was performed to identify risk factors for development of infection. Logistic regression was performed to identify risks for unfavorable neurologic outcome at 3 months, defined as a Glasgow Outcome Scale score of 1–3.
Of the 248 patients with SAH, 70 (28.2%) developed at least 1 infection; the most frequent site of infection was respiratory (57.1%), primary bloodstream (16%), and urinary tract infections (15.7%). Twenty-eight patients (11.3% of all patients) had at least 1 episode of septic shock. Infected patients had a higher unfavorable outcome rate (60.0% vs. 33.3%; P = 0.001). Diabetes mellitus (subdistribution hazard ratio, 1.79; 95% confidence interval [CI], 1.03–3.13) and intracranial hypertension (subdistribution hazard ratio, 1.92; 95% CI, 1.14–3.25) were independently associated with the occurrence of infections. Septic shock (odds ratio, 6.36; 95% CI, 1.24–32.51; P = 0.02) was independently associated with unfavorable outcome.
Infections in patients with SAH are prevalent, especially pneumonia. Septic shock is associated with a poor neurologic outcome in this group of patients.
In Reply to the Letter to the Editor Regarding “Effect of Early Brain Infarction After Subarachnoid Hemorrhage: A Systematic Review and Meta-Analysis”
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Clinical Characteristics and Outcomes of Patients with Aneurysmal Subarachnoid Hemorrhage: A Prospective Multicenter Study in a Middle-Income Country
2023, Neurocritical Care

View all citing articles on Scopus

: Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Original ArticleEffect of Early Brain Infarction After Subarachnoid Hemorrhage: A Systematic Review and Meta-Analysis

Highlights

Objective

Methods

Results

Conclusions

Introduction

Section snippets

Search Strategy and Selection Criteria

Results

Discussion

Conclusion

Lancet

Prog Neurobiol

Advances in the understanding of delayed cerebral ischaemia after aneurysmal subarachnoid haemorrhage

F1000Res

Cerebral vasospasm after subarachnoid hemorrhage: the emerging revolution

Nat Clin Pract Neurol

Management of delayed cerebral ischemia after subarachnoid hemorrhage

Crit Care

Signaling pathways for early brain injury after subarachnoid hemorrhage

J Cereb Blood Flow Metab

Mechanisms of early brain injury after subarachnoid hemorrhage

J Cereb Blood Flow Metab

Cochrane Handbook for Systematic Reviews of Interventions

Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement

PLoS Med

Methodological index for non-randomized studies (MINORS): development and validation of a new instrument

ANZ J Surg

Critical care management of patients following aneurysmal subarachnoid hemorrhage: recommendations from the Neurocritical Care Society's Multidisciplinary Consensus Conference

Neurocrit Care

Early ischemic lesion on computed tomography: predictor of poor outcome among survivors of aneurysmal subarachnoid hemorrhage

J Neurosurg

Early cerebral infarction as a risk factor for poor outcome after aneurysmal subarachnoid haemorrhage

Eur J Neurol

Original Article
Effect of Early Brain Infarction After Subarachnoid Hemorrhage: A Systematic Review and Meta-Analysis