Cytotoxic Edema and Adverse Clinical Outcomes in Patients with Intracerebral Hemorrhage

Overview

Journal Neurocrit Care

Specialty Critical Care

Date 2022 Sep 30

PMID 36180765

Authors

Na Li

Jiahuan Guo

Kaijiang Kang

Jia Zhang

Zhe Zhang

Lijun Liu

Xinmin Liu

Yang Du

Yu Wang

Xingquan Zhao

Affiliations

Soon will be listed here.

Abstract

Background: Cytotoxic edema (CE) is an important form of perihematomal edema (PHE), which is a surrogate marker of secondary injury after intracerebral hemorrhage (ICH). However, knowledge about CE after ICH is insufficient. Whether CE has adverse effects on clinical outcomes of patients with ICH remains unknown. Therefore, we aimed to investigate the temporal pattern of CE and its association with clinical outcomes in patients with ICH.

Methods: Data were derived from a randomized controlled study (comparing the deproteinized calf blood extract with placebo in patients with ICH). Intervention in this original study did not show any impact on hematoma and PHE volume, presence of CE, or clinical outcomes. We conducted our analysis in 20 patients who underwent magnetic resonance imaging with diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) images at day 3 and within 7-12 days after symptom onset. CE was defined as an elevated DWI b1000 signal and an ADC value reduced by > 10% compared with the mirror area of interest in the perihematomal region. The modified Rankin Scale (mRS), National Institutes of Health Stroke Scale (NIHSS), and Barthel Index (BI) were performed face to face at 30-day and 90-day follow-ups after ICH onset to assess the clinical outcomes of the patients.

Results: CE was detected in nearly two thirds of patients with ICH in our study and seemed to be reversible. CE within 7-12 days, rather than at day 3 after symptom onset, was associated with poor clinical outcome (mRS 3-6) at the 30-day follow-up (P = 0.020). In addition, compared with those without CE, patients with CE within 7-12 days had more severe neurological impairment measured by NIHSS score (P = 0.024) and worse daily life quality measured by BI (P = 0.004) at both the 30- and 90-day follow-ups.

Conclusions: CE appears in the acute phase of ICH and might be reversible. CE within 7-12 days post ICH was related to poor outcomes, which provides a novel therapeutic target for ICH intervention.

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References

Chen S, Peng J, Sherchan P, Ma Y, Xiang S, Yan F . TREM2 activation attenuates neuroinflammation and neuronal apoptosis via PI3K/Akt pathway after intracerebral hemorrhage in mice. J Neuroinflammation. 2020; 17(1):168. PMC: 7257134. DOI: 10.1186/s12974-020-01853-x. View

Xie L, Wang Y, Chen Z . LncRNA Blnc1 mediates the permeability and inflammatory response of cerebral hemorrhage by regulating the PPAR-γ/SIRT6/FoxO3 pathway. Life Sci. 2020; 267:118942. DOI: 10.1016/j.lfs.2020.118942. View

Ni W, Mao S, Xi G, Keep R, Hua Y . Role of Erythrocyte CD47 in Intracerebral Hematoma Clearance. Stroke. 2016; 47(2):505-11. PMC: 4729651. DOI: 10.1161/STROKEAHA.115.010920. View

Tsai Y, Hsu L, Weng H, Lee M, Yang J, Lin C . Voxel-based analysis of apparent diffusion coefficient in perihaematomal oedema: associated factors and outcome predictive value for intracerebral haemorrhage. BMJ Open. 2011; 1(1):e000230. PMC: 3227805. DOI: 10.1136/bmjopen-2011-000230. View

Ironside N, Chen C, Ding D, Mayer S, Sander Connolly Jr E . Perihematomal Edema After Spontaneous Intracerebral Hemorrhage. Stroke. 2019; 50(6):1626-1633. DOI: 10.1161/STROKEAHA.119.024965. View

Chen Y, Chen S, Chang J, Wei J, Feng M, Wang R . Perihematomal Edema After Intracerebral Hemorrhage: An Update on Pathogenesis, Risk Factors, and Therapeutic Advances. Front Immunol. 2021; 12:740632. PMC: 8560684. DOI: 10.3389/fimmu.2021.740632. View

Obrenovitch T, Urenjak J . Is high extracellular glutamate the key to excitotoxicity in traumatic brain injury?. J Neurotrauma. 1997; 14(10):677-98. DOI: 10.1089/neu.1997.14.677. View

Wahl F, Obrenovitch T, Hardy A, Plotkine M, Boulu R, Symon L . Extracellular glutamate during focal cerebral ischaemia in rats: time course and calcium dependency. J Neurochem. 1994; 63(3):1003-11. DOI: 10.1046/j.1471-4159.1994.63031003.x. View

Winkler E, Minter D, Yue J, Manley G . Cerebral Edema in Traumatic Brain Injury: Pathophysiology and Prospective Therapeutic Targets. Neurosurg Clin N Am. 2016; 27(4):473-88. DOI: 10.1016/j.nec.2016.05.008. View

10.

Brunswick A, Hwang B, Appelboom G, Hwang R, Piazza M, Connolly Jr E . Serum biomarkers of spontaneous intracerebral hemorrhage induced secondary brain injury. J Neurol Sci. 2012; 321(1-2):1-10. DOI: 10.1016/j.jns.2012.06.008. View

11.

Ren H, Kong Y, Liu Z, Zang D, Yang X, Wood K . Selective NLRP3 (Pyrin Domain-Containing Protein 3) Inflammasome Inhibitor Reduces Brain Injury After Intracerebral Hemorrhage. Stroke. 2017; 49(1):184-192. PMC: 5753818. DOI: 10.1161/STROKEAHA.117.018904. View

12.

Yang J, Arima H, Wu G, Heeley E, Delcourt C, Zhou J . Prognostic significance of perihematomal edema in acute intracerebral hemorrhage: pooled analysis from the intensive blood pressure reduction in acute cerebral hemorrhage trial studies. Stroke. 2015; 46(4):1009-13. DOI: 10.1161/STROKEAHA.114.007154. View

13.

Babu R, Bagley J, Di C, Friedman A, Adamson C . Thrombin and hemin as central factors in the mechanisms of intracerebral hemorrhage-induced secondary brain injury and as potential targets for intervention. Neurosurg Focus. 2012; 32(4):E8. DOI: 10.3171/2012.1.FOCUS11366. View

14.

Kidwell C, Saver J, Mattiello J, Warach S, Liebeskind D, Starkman S . Diffusion-perfusion MR evaluation of perihematomal injury in hyperacute intracerebral hemorrhage. Neurology. 2001; 57(9):1611-7. DOI: 10.1212/wnl.57.9.1611. View

15.

Staykov D, Wagner I, Volbers B, Hauer E, Doerfler A, Schwab S . Natural course of perihemorrhagic edema after intracerebral hemorrhage. Stroke. 2011; 42(9):2625-9. DOI: 10.1161/STROKEAHA.111.618611. View

16.

Li N, Liu Y, Ma L, Worthmann H, Wang Y, Wang Y . Association of molecular markers with perihematomal edema and clinical outcome in intracerebral hemorrhage. Stroke. 2013; 44(3):658-63. DOI: 10.1161/STROKEAHA.112.673590. View

17.

Huang F, Xi G, Keep R, Hua Y, Nemoianu A, Hoff J . Brain edema after experimental intracerebral hemorrhage: role of hemoglobin degradation products. J Neurosurg. 2002; 96(2):287-93. DOI: 10.3171/jns.2002.96.2.0287. View

18.

Xue M, Yong V . Neuroinflammation in intracerebral haemorrhage: immunotherapies with potential for translation. Lancet Neurol. 2020; 19(12):1023-1032. DOI: 10.1016/S1474-4422(20)30364-1. View

19.

Schrag M, Kirshner H . Management of Intracerebral Hemorrhage: JACC Focus Seminar. J Am Coll Cardiol. 2020; 75(15):1819-1831. DOI: 10.1016/j.jacc.2019.10.066. View

20.

Chen L, Xu M, Yan S, Luo Z, Tong L, Lou M . Insufficient cerebral venous drainage predicts early edema in acute intracerebral hemorrhage. Neurology. 2019; 93(15):e1463-e1473. DOI: 10.1212/WNL.0000000000008242. View