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A) Example of hematoma and perihematoma edema regions of interest (ROIs). The ROIs were drawn on the noncontrast computed tomography (CT) and transferred to perfusion maps. (B) Maps of cerebral blood flow (CBF), cerebral blood volume (CBV), and time to peak of the impulse response curve (TMAX) from an ICH ADAPT study patient randomized to a target systolic BP <150 mm Hg.
Source publication
Statin therapy has been associated with improved cerebral blood flow (CBF) and decreased perihematoma edema in animal models of intracerebral hemorrhage (ICH). We aimed to assess the relationship between statin use and cerebral hemodynamics in ICH patients. A post hoc analysis of 73 ICH patients enrolled in the Intracerebral Hemorrhage Acutely Decr...
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Context 1
... Both hematoma and edema region of interest measurements were completed independently by two investigators (RM and BG) on NCCTs at all time points (baseline, 2, and 24 hours). Hematoma and total ICH (calculated as hematoma+intraven- tricular hemorrhage) volumes were measured using planimetric semiauto- matic thresholding segmentation techniques, as previously described ( Figure 1). 16 Perihematoma edema regions were independently drawn manually by the two raters. ...
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Citations
... Prior clinical and preclinical studies demonstrated that MMP-9 rises abnormally in the brain and blood after ICH, leading to blood-brain barrier disruption, cerebral edema, neuronal injury, and worse clinical outcome. 20,[31][32][33][34][35][36][37] In contrast, it is shown that VEGF promoted neovascularization and oxygen delivery following neuronal injury. 19 Hence, as suggested by animal and human models, increased VEGF levels have a neuroprotective effect after neurovascular Injury. ...
Background
Prior studies have shown statins provide neuroprotection by targeting secondary brain injury pathways and regulating cytokine production. We aimed to evaluate the association between statin administration and molecular outcomes in acute Intracranial hemorrhages (ICHs).
Methods
Adult patients with acute spontaneous ICH were recruited and randomly allocated into two groups: group A received atorvastatin (40 mg/day) orally in addition to routine antihypertensive medications, while group B only received routine antihypertensives. Serum levels of matrix metalloproteinase-9 (MMP-9), and vascular endothelial growth factor (VEGF), as primary outcomes, were measured at baseline, and after 45 days.
Results
Thirty-nine ICH patients (group A: 20; group B: 19) were analyzed. A notable elevation in VEGF and a reduction in MMP-9 levels were detected in group A compared to those in group B (P-value = 0.024 and 0.008, respectively).
Conclusions
Our data suggest that atorvastatin in the acute phase of ICH could improve the serum levels of neuroprotective molecular biomarkers.
... PSM, propensity score matching the Canadian Stroke Network.16 A post-hoc analysis of 73 ICH patients enrolled in the Intracerebral Hemorrhage Acutely Decreasing Arterial Pressure Trial (ICH ADAPT) showed similar median hematoma volumes in statin users compared to non-treated patients.17 A ...
The relationship between statins and intracerebral hemorrhage outcomes is unclear. We aimed to compare the in‐hospital mortality and the rates of evacuation of intracranial hematoma in patients with primary intracerebral hemorrhage between prior statins users and non‐users. A retrospective study was conducted and data were derived from the Chinese Stroke Center Consortium (CSCA). Patients aged 50 years or older with a diagnosis of primary intracerebral hemorrhage were included. Demographic data, medical history, NIHSS, and Glasgow coma scale (GCS) score were collected. Outcome measures included death at discharge and evacuation of intracranial hematoma. Multivariable logistic regression analyses and propensity score matching analyses were used to investigate the relationship between prior statins use and the clinical outcomes. The final study population included 66,263 patients. Multivariable logistics analyses showed that prior statins use was not associated with in‐hospital mortality for primary intracerebral hemorrhage (adjusted OR 0.78, 95% CI 0.61–1.01), but reduced the proportion of patients undergoing evacuation of intracranial hematoma (adjusted OR 0.70, 95% CI 0.61–0.82), and propensity score matching analyses yielded similar results. Prior statins use is not associated with in‐hospital mortality, but reduced the rates of evacuation of intracranial hematoma. image
... 7,8 However, these results may harbor residual bias by indication, why the impact of early statin initiation on secondary injury after the initial ICH needs to be established. 9,10 The European Stroke Organization, therefore, defined the issue of when statins should be (re-)started after ICH as major priority in ICH research. 11 The present study explored the hypothesis that statin treatment may influence hematoma characteristics (1), extent of perihemorrhagic edema (PHE; 2), occurrence of remote symptomatic seizures (3), cardiovascular events and functional recovery (4) following ICH. ...
... 10,24 PHE has only been investigated during the first 24 to 48 hours after the ICH event, which is why the effect of statin continuation, discontinuation, or initiation on edema extent have not been evaluated so far and statins may potentially even impair functional outcome by increased edema formation. 10,23 Therefore, the European Stroke Organisation defined the issue of when statins should be (re-) started after ICH as major priority in ICH research. 11 By evaluating the maximal extent of PHE formation, that is, peak PHE, we demonstrate that initiation of statin therapy in patients with ICH without such premedication seems to increase peak PHE and may affect functional outcome by aggravating secondary brain injury. ...
Background and Purpose
The impact of statins on hematoma characteristics, perihemorrhagic edema (PHE), cardiovascular events, seizures, and functional recovery in patients with intracerebral hemorrhage (ICH) is insufficiently studied.
Methods
Patients with ICH of the prospective UKER-ICH (Universitätsklinikum Erlangen Cohort of Patients With Spontaneous Intracerebral Hemorrhage) study (URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03183167) were analyzed by multivariable regression modeling and propensity score matching, and PHE volumes were volumetrically assessed. Outcomes comprised hematoma characteristics, the impact of continuation, discontinuation, and initiation of statins on peak PHE extent, and the influence of statin treatment on the occurrence of seizures, cardiovascular adverse events, and functional recovery after ICH.
Results
A total of 1275 patients with ICH with information on statin treatment were analyzed. Statin treatment on hospital admission (21.7%) was associated with higher rates of lobar versus nonlobar ICH (odds ratio, 1.57 [1.03–2.40]; P =0.038). Initiation of statins after ICH was associated with increased peak PHE (β=0.12, SE=0.06, P =0.008), whereas continuation versus discontinuation of prior statin treatment was not significantly associated with edema formation ( P >0.10). There were no significant differences in the incidence of remote symptomatic seizures according to statin exposure during follow-up (statins: 11.5% versus no statins: 7.8%, subdistribution hazard ratio: 1.15 [0.80–1.66]; P =0.512). Patients on statins revealed less cardiovascular adverse events and more frequently functional recovery after 12 months (functional recovery: 57.7% versus 45.0%, odds ratio 1.67 [1.09–2.56]; P =0.019).
Conclusions
Among statin users, lobar ICH occurs more frequently as compared with nonstatin users. While continuation of prior statin treatment appears to be safe regarding PHE formation, the initiation of statins during the first days after ICH may increase PHE extent. However, statins should be initiated thereafter (eg, at hospital discharge) to prevent cardiovascular events and potentially improve functional recovery.
... Whereby, new therapy for improving the outcome of ICH is urgently to be explored. Brain edema in the perihematoma area was reported to contribute a lot on ICHmediated brain damage and closely associated with poor clinical outcomes, such as deterioration or even death [2][3][4]. Brain edema destroys the blood-brain barrier (BBB), resulting in inflammatory factors releasing into the blood circulation, further leading to the dysfunction of cerebral blood flow (CBF) automatic regulation, and finally, reducing the CBF in the perihematoma area [5]. Therefore, CBF improvement and brain tissue protection in the perihematoma area may be important targets in ICH treatment. ...
Background
All of the existing medication and surgical therapies currently cannot completely inhibit intracerebral hemorrhage (ICH)-mediated brain damage, resulting in disability in different degrees in the involved patients. Normobaric oxygenation (NBO) was reported attenuating ischemic brain injury. Herein, we aimed to explore the safety and efficacy of NBO on rescuing the damaged brain tissues secondary to acute ICH, especially those in the perihematoma area being threatened by ischemia and hypoxia.
Methods
A total of 150 patients confirmed as acute spontaneous ICH by computed tomography (CT) within 6 h after symptoms onset, will enroll in this study after signing the informed consent, and enter into the NBO group or control group randomly according to a random number. In the NBO group, patients will inhale high-flow oxygen (8 L/min, 1 h each time for 6 cycles daily) and intake low-flow oxygen (2 L/min) in intermittent periods by mask for a total of 7 days. While in the control group, patients will breathe in only low-flow oxygen (2 L/min) by mask for 7 consecutive days. Computed tomography and perfusion (CT/CTP) will be used to evaluate cerebral perfusion status and brain edema. CT and CTP maps in the two groups at baseline and day 7 and 14 after NBO or low-flow oxygen control will be compared. The primary endpoint is mRS at both Day14 post-ICH and the end of the 3rd month follow-up. The secondary endpoints include NIHSS and plasma biomarkers at baseline and Day-1, 7, and 14 after treatment, as well as the NIHSS at the end of the 3rd month post-ICH and the incidence of bleeding recurrence and the mortalities within 3 months post-ICH.
Discussion
This study will provide preliminary clinical evidence about the safety and efficacy of NBO on correcting acute ICH and explore some mechanisms accordingly, to offer reference for larger clinical trials in the future.
Trial registration
ClinicalTrials.gov NCT04144868 . Retrospectively registered on October 29, 2019.
... Combination of statins and deferoxamine showed a greater effect on PHE and hematoma volume than either agent alone (95). Unlike animal studies, statin use in humans has been linked to increased PHE volume in ICH patients with no effect on CBF (96). One study of 303 ICH patients with 71 statin users showed higher initial and final hematoma volume in statin users (97). ...
Intracerebral hemorrhage (ICH) is a medical emergency, which often leads to severe disability and death. ICH-related poor outcomes are due to primary injury causing structural damage and mass effect and secondary injury in the perihemorrhagic region over several days to weeks. Secondary injury after ICH can be due to hematoma expansion (HE) or a consequence of repair pathway along the continuum of neuroinflammation, neuronal death, and perihemorrhagic edema (PHE). This review article is focused on PHE and HE and will cover the animal studies, related human studies, and clinical trials relating to these mechanisms of secondary brain injury in ICH patients.
Statins, otherwise known as 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are a pharmacological class of medication frequently utilized in the treatment of dyslipidemia. These agents have shown some promise in preclinical and early phase trials for neuroprotection after acute neurological injury. While the primary mechanism of action of statins is inhibition of the HMG-CoA enzyme, the rate-limiting enzyme in cholesterol synthesis, resulting in an increased expression of low-density lipoprotein (LDL) receptors and ultimately a reduction in serum LDL, statins have been reported to have several pleiotropic effects including improvement in endothelial function, reducing inflammation, inhibition of platelet aggregation, and anticoagulant properties. This chapter describes the available evidence to date examining statin pharmacotherapy for neuroprotection after traumatic brain injury, acute ischemic stroke, intracerebral hemorrhage, and aneurysmal subarachnoid hemorrhage.
Background Lipid levels and statins may influence intracerebral hemorrhage (ICH) occurrence and hematoma characteristics. Furthermore, statins are reported to exert effects on perihemorrhagic edema (PHE) formation, cardiovascular events, seizures and functional recovery. However, previous studies have several shortcomings and the relevance of lipid levels and statins in ICH is not sufficiently understood. Methods Patients of the UKER-ICH (Universitätsklinikum Erlangen Cohort of Patients with Spontaneous Intracerebral Hemorrhage) cohort study between 01 January 2006 and 31 December 2015 were included to analyze the impact of lipid levels and statins on hematoma characteristics, PHE, early symptomatic seizures (≤7 days after the bleeding event) and remote seizures (>7 days), cardiovascular adverse events and functional recovery after ICH. Multivariable regression models were adjusted for differences in baseline characteristics (analysis of hematoma characteristics), parameters associated with functional outcome and improvement (analysis of functional recovery), age and ICH volume (analysis of PHE). Cox proportional hazards models were adjusted for lobar ICH, age >65 years and ICH volume >10 ml (analysis seizures) and parameters associated with cardiovascular risk factors (analysis of cardiovascular adverse events). Results Overall, 1275 ICH patients of the UKER-ICH cohort study were analyzed. There were significant differences regarding hematoma location in patients with low versus high LDL levels (deep ICH: 81/145 [55.9%] versus 61/141 [43.3%], p<0.05), but no relevant associations between lipid levels and hematoma volume. Statin medication at hospital admission (277/1275 [21.7%]) was associated with lobar hematoma location (p<0.01). Regarding different statin regimes, initiation of statins was associated with increased perihemorrhagic edema extent (p<0.01), continuation versus discontinuation of statin premedication was not significantly associated with PHE (p>0.200). There were no significant differences according to statin exposure regarding early seizures (statins: 10.1% versus no statins: 11.9%; adjusted hazard ratio [aHR]: 0.80 [0.53-1.22], p=0.304) and remote seizures during 5 years after ICH (p>0.20). Cardiovascular adverse events occurred less often in patients on statin therapy, whereas functional recovery was more frequent among patients on statin therapy (57.7% versus 45.0%, p<0.05). Parts of the present study are being published in the STROKE journal. Conclusions Elevated lipid levels might have protective effects against the occurrence of deep ICH location, while statins are associated with higher rates of lobar ICH. Statin continuation appears safe regarding PHE formation, whereas initiation of statins during the acute phase after ICH may increase edema extent. Therefore, statins should be initiated thereafter (e.g. after hospital discharge) to prevent cardiovascular adverse events and potentially improve functional recovery.
Statins, a common drug class for treatment of dyslipidemia, may be neuroprotective for spontaneous intracerebral hemorrhage (ICH) by targeting secondary brain injury pathways in the surrounding brain parenchyma. Statin-mediated neuroprotection may stem from downregulation of mevalonate and its derivatives, targeting key cell signaling pathways that control proliferation, adhesion, migration, cytokine production, and reactive oxygen species generation. Preclinical studies have consistently demonstrated the neuroprotective and recovery enhancement effects of statins, including improved neurologic function, reduced cerebral edema, increased angiogenesis and neurogenesis, accelerated hematoma clearance, and decreased inflammatory cell infiltration. Retrospective clinical studies have reported reduced perihematomal edema, lower mortality rates, and improved functional outcomes in patients who were taking statins before ICH. Several clinical studies have also observed lower mortality rates and improved functional outcomes in patients who were continued or initiated on statins after ICH. Subgroup analysis of a previous randomized trial has raised concerns of a potentially elevated risk of recurrent ICH in patients with previous hemorrhagic stroke who are administered statins. However, most statin trials failed to show an association between statin use and increased hemorrhagic stroke risk. Variable statin dosing, statin use in the pre-ICH setting, and selection biases have limited rigorous investigation of the effects of statins on post-ICH outcomes. Future prospective trials are needed to investigate the association between statin use and outcomes in ICH.
