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Pathophysiology and treatment of cerebral edema in traumatic brain injury.

ABSTRACT: Cerebral edema (CE) and resultant intracranial hypertension are associated with unfavorable prognosis in traumatic brain injury (TBI). CE is a leading cause of in-hospital mortality, occurring in >60% of patients with mass lesions, and ?15% of those with normal initial computed tomography scans. After treatment of mass lesions in severe TBI, an important focus of acute neurocritical care is evaluating and managing the secondary injury process of CE and resultant intracranial hypertension. This review focuses on a contemporary understanding of various pathophysiologic pathways contributing to CE, with a subsequent description of potential targeted therapies. There is a discussion of identified cellular/cytotoxic contributors to CE, as well as mechanisms that influence blood-brain-barrier (BBB) disruption/vasogenic edema, with the caveat that this distinction may be somewhat artificial since molecular processes contributing to these pathways are interrelated. While an exhaustive discussion of all pathways with putative contributions to CE is beyond the scope of this review, the roles of some key contributors are highlighted, and references are provided for further details. Potential future molecular targets for treating CE are presented based on pathophysiologic mechanisms. We thus aim to provide a translational synopsis of present and future strategies targeting CE after TBI in the context of a paradigm shift towards precision medicine. This article is part of the Special Issue entitled "Novel Treatments for Traumatic Brain Injury".

SUBMITTER: Jha RM

PROVIDER: S-EPMC6309515 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Pathophysiology and treatment of cerebral edema in traumatic brain injury.

Jha Ruchira M RM Kochanek Patrick M PM Simard J Marc JM

Neuropharmacology 20180804 Pt B

Cerebral edema (CE) and resultant intracranial hypertension are associated with unfavorable prognosis in traumatic brain injury (TBI). CE is a leading cause of in-hospital mortality, occurring in >60% of patients with mass lesions, and ∼15% of those with normal initial computed tomography scans. After treatment of mass lesions in severe TBI, an important focus of acute neurocritical care is evaluating and managing the secondary injury process of CE and resultant intracranial hypertension. This r ...[more]

PMID: 30086289

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Project description:OBJECTIVES:Cerebral edema is a key poor prognosticator in traumatic brain injury. There are no biomarkers identifying patients at-risk, or guiding mechanistically-precise therapies. Sulfonylurea receptor-1-transient receptor potential cation channel M4 is upregulated only after brain injury, causing edema in animal studies. We hypothesized that sulfonylurea receptor-1 is measurable in human cerebrospinal fluid after severe traumatic brain injury and is an informative biomarker of edema and outcome. DESIGN:A total of 119 cerebrospinal fluid samples were collected from 28 severe traumatic brain injury patients. Samples were retrieved at 12, 24, 48, 72 hours and before external ventricular drain removal. Fifteen control samples were obtained from patients with normal pressure hydrocephalus. Sulfonylurea receptor- 1 was quantified by enzyme-linked immunosorbent assay. Outcomes included CT edema, intracranial pressure measurements, therapies targeting edema, and 3-month Glasgow Outcome Scale score. MAIN RESULTS:Sulfonylurea receptor-1 was present in all severe traumatic brain injury patients (mean = 3.54 ± 3.39 ng/mL, peak = 7.13 ± 6.09 ng/mL) but undetectable in all controls (p < 0.001). Mean and peak sulfonylurea receptor-1 was higher in patients with CT edema (4.96 ± 1.13 ng/mL vs 2.10 ± 0.34 ng/mL; p = 0.023). There was a temporal delay between peak sulfonylurea receptor-1 and peak intracranial pressure in 91.7% of patients with intracranial hypertension. There was no association between mean/peak sulfonylurea receptor-1 and mean/peak intracranial pressure, proportion of intracranial pressure greater than 20 mm Hg, use of edema-directed therapies, decompressive craniotomy, or 3-month Glasgow Outcome Scale. However, decreasing sulfonylurea receptor-1 trajectories between 48 and 72 hours were significantly associated with improved cerebral edema and clinical outcome. Area under the multivariate model receiver operating characteristic curve was 0.881. CONCLUSIONS:This is the first report quantifying human cerebrospinal fluid sulfonylurea receptor-1. Sulfonylurea receptor-1 was detected in severe traumatic brain injury, absent in controls, correlated with CT-edema and preceded peak intracranial pressure. Sulfonylurea receptor-1 trajectories between 48 and 72 hours were associated with outcome. Because a therapy inhibiting sulfonylurea receptor-1 is available, assessing cerebrospinal fluid sulfonylurea receptor-1 in larger studies is warranted to evaluate our exploratory findings regarding its diagnostic, and monitoring utility, as well as its potential to guide targeted therapies in traumatic brain injury and other diseases involving cerebral edema.

Project description:Purpose of reviewStandard clinical protocols for treating cerebral edema and intracranial hypertension after severe TBI have remained remarkably similar over decades. Cerebral edema and intracranial hypertension are treated interchangeably when in fact intracranial pressure (ICP) is a proxy for cerebral edema but also other processes such as extent of mass lesions, hydrocephalus, or cerebral blood volume. A complex interplay of multiple molecular mechanisms results in cerebral edema after severe TBI, and these are not measured or targeted by current clinically available tools. Addressing these underpinnings may be key to preventing or treating cerebral edema and improving outcome after severe TBI.Recent findingsThis review begins by outlining basic principles underlying the relationship between edema and ICP including the Monro-Kellie doctrine and concepts of intracranial compliance/elastance. There is a subsequent brief discussion of current guidelines for ICP monitoring/management. We then focus most of the review on an evolving precision medicine approach towards cerebral edema and intracranial hypertension after TBI. Personalization of invasive neuromonitoring parameters including ICP waveform analysis, pulse amplitude, pressure reactivity, and longitudinal trajectories are presented. This is followed by a discussion of cerebral edema subtypes (continuum of ionic/cytotoxic/vasogenic edema and progressive secondary hemorrhage). Mechanisms of potential molecular contributors to cerebral edema after TBI are reviewed. For each target, we present findings from preclinical models, and evaluate their clinical utility as biomarkers and therapeutic targets for cerebral edema reduction. This selection represents promising candidates with evidence from different research groups, overlap/inter-relatedness with other pathways, and clinical/translational potential. We outline an evolving precision medicine and translational approach towards cerebral edema and intracranial hypertension after severe TBI.

Project description:Cerebral edema is critical to morbidity/mortality in traumatic brain injury (TBI) and is worsened by hypotension. Glibenclamide may reduce cerebral edema by inhibiting sulfonylurea receptor-1 (Sur1); its effect on diffuse cerebral edema exacerbated by hypotension/resuscitation is unknown. We aimed to determine if glibenclamide improves pericontusional and/or diffuse edema in controlled cortical impact (CCI) (5m/sec, 1?mm depth) plus hemorrhagic shock (HS) (35?min), and compare its effects in CCI alone. C57BL/6 mice were divided into five groups (n?=?10/group): naïve, CCI+vehicle, CCI+glibenclamide, CCI+HS+vehicle, and CCI+HS+glibenclamide. Intravenous glibenclamide (10?min post-injury) was followed by a subcutaneous infusion for 24?h. Brain edema in injured and contralateral hemispheres was subsequently quantified (wet-dry weight). This protocol brain water (BW)?=?80.4% vehicle vs. 78.3% naïve, p?<?0.01) but was not reduced by glibenclamide (I%BW?=?80.4%). Ipsilateral edema also developed in CCI alone (I%BW?=?80.2% vehicle vs. 78.3% naïve, p?<?0.01); again unaffected by glibenclamide (I%BW?=?80.5%). Contralateral (C) %BW in CCI+HS was increased in vehicle (78.6%) versus naive (78.3%, p?=?0.02) but unchanged in CCI (78.3%). At 24?h, glibenclamide treatment in CCI+HS eliminated contralateral cerebral edema (C%BW?=?78.3%) with no difference versus naïve. By 72?h, contralateral cerebral edema had resolved (C%BW?=?78.5?±?0.09% vehicle vs. 78.3?±?0.05% naïve). Glibenclamide decreased 24?h contralateral cerebral edema in CCI+HS. This beneficial effect merits additional exploration in the important setting of TBI with polytrauma, shock, and resuscitation. Contralateral edema did not develop in CCI alone. Surprisingly, 24?h of glibenclamide treatment failed to decrease ipsilateral edema in either model. Interspecies dosing differences versus prior studies may play an important role in these findings. Mechanisms underlying brain edema may differ regionally, with pericontusional/osmolar swelling refractory to glibenclamide but diffuse edema (via Sur1) from combined injury and/or resuscitation responsive to this therapy. TBI phenotype may mandate precision medicine approaches to treat brain edema.

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Pathophysiology and treatment of cerebral edema in traumatic brain injury.

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Pathophysiology and treatment of cerebral edema in traumatic brain injury.

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