Cerebral Edema in Traumatic Brain Injury: a Historical Framework for Current Therapy.
Ontology highlight
ABSTRACT: Purpose of review
The purposes of this narrative review are to (1) summarize a contemporary view of cerebral edema pathophysiology, (2) present a synopsis of current management strategies in the context of their historical roots (many of which date back multiple centuries), and (3) discuss contributions of key molecular pathways to overlapping edema endophenotypes. This may facilitate identification of important therapeutic targets.Recent findings
Cerebral edema and resultant intracranial hypertension are major contributors to morbidity and mortality following traumatic brain injury. Although Starling forces are physical drivers of edema based on differences in intravascular vs extracellular hydrostatic and oncotic pressures, the molecular pathophysiology underlying cerebral edema is complex and remains incompletely understood. Current management protocols are guided by intracranial pressure measurements, an imperfect proxy for cerebral edema. These include decompressive craniectomy, external ventricular drainage, hyperosmolar therapy, hypothermia, and sedation. Results of contemporary clinical trials assessing these treatments are summarized, with an emphasis on the gap between intermediate measures of edema and meaningful clinical outcomes. This is followed by a brief statement summarizing the most recent guidelines from the Brain Trauma Foundation (4th edition). While many molecular mechanisms and networks contributing to cerebral edema after TBI are still being elucidated, we highlight some promising molecular mechanism-based targets based on recent research including SUR1-TRPM4, NKCC1, AQP4, and AVP1.Summary
This review outlines the origins of our understanding of cerebral edema, chronicles the history behind many current treatment approaches, and discusses promising molecular mechanism-based targeted treatments.
SUBMITTER: Zusman BE
PROVIDER: S-EPMC8223756 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description: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".
| S-EPMC6309515 | biostudies-literature
Project description:Traumatic brain injury (TBI) could result in edema and cause an increase in intracranial pressure of the brain resulting in mortality and morbidity. Although there is hyperosmolarity therapy available for this pathophysiological event, it remains controversial. Recently, several groups have shown docosahexaenoic acid (DHA) to improve functional and histological outcomes following brain injury based on reduction of neuroinflammation and apoptosis. However, the effect of DHA on blood-brain barrier (BBB) dysfunction after brain injury has not been fully studied. Here, a controlled cortical impact rat model was used to test the effect of a single dose of DHA administered 30 min post injury. Modified neurological severity score (mNSS) and forelimb asymmetry were used to determine the functional outcomes. Neuroimaging and histology were used to characterize the edema and BBB dysfunction. The study showed that DHA-treated TBI rats had better mNSS and forelimb asymmetry score than vehicle-treated TBI rats. Temporal analysis of edema using MRI revealed a significant reduction in edema level with DHA treatment compared to vehicle in TBI rats. Histological analysis using immunoglobulin G (IgG) extravasation showed that there was less extravasation, which corresponded with a reduction in aquaporin 4 and astrocytic metalloprotease 9 expression, and greater endothelial occludin expression in the peri-contusional site of the TBI rat brain treated with DHA in comparison to vehicle treatment. In conclusion, the study shows that DHA can exert its functional improvement by prevention of the edema formation via prevention of BBB dysfunction after TBI.
| S-EPMC7503959 | biostudies-literature
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.
| S-EPMC5550829 | biostudies-literature
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.
| S-EPMC6589108 | biostudies-literature
Project description:Edema is an important target for clinical intervention after traumatic brain injury (TBI). We used in vivo cellular resolution imaging and electrophysiological recording to examine the ionic mechanisms underlying neuronal edema and their effects on neuronal and network excitability after controlled cortical impact (CCI) in mice. Unexpectedly, we found that neuronal edema 48 hours after CCI was associated with reduced cellular and network excitability, concurrent with an increase in the expression ratio of the cation-chloride cotransporters (CCCs) NKCC1 and KCC2. Treatment with the CCC blocker bumetanide prevented neuronal swelling via a reversal in the NKCC1/KCC2 expression ratio, identifying altered chloride flux as the mechanism of neuronal edema. Importantly, bumetanide treatment was associated with increased neuronal and network excitability after injury, including increased susceptibility to spreading depolarizations (SDs) and seizures, known agents of clinical worsening after TBI. Treatment with mannitol, a first-line edema treatment in clinical practice, was also associated with increased susceptibility to SDs and seizures after CCI, showing that neuronal volume reduction, regardless of mechanism, was associated with an excitability increase. Finally, we observed an increase in excitability when neuronal edema normalized by 1 week after CCI. We conclude that neuronal swelling may exert protective effects against damaging excitability in the aftermath of TBI and that treatment of edema has the potential to reverse these effects.
| S-EPMC7598047 | biostudies-literature
Project description:Non-penetrating or mild traumatic brain injury (mTBI) is commonly experienced in accidents, the battlefield and in full-contact sports. Astrocyte cellular edema is one of the major factors that leads to high morbidity post-mTBI. Various studies have reported an upregulation of aquaporin-4 (AQP4), a water channel protein, following brain injury. AZA is an antiepileptic drug that has been shown to inhibit AQP4 expression and in this study we investigate the drug as a therapeutic to mitigate the extent of mTBI induced cellular edema. We hypothesized that mTBI-mediated astrocyte dysfunction, initiated by increased intracellular volume, could be reduced when treated with AZA. We tested our hypothesis in a three-dimensional in vitro astrocyte model of mTBI. Samples were subject to no stretch (control) or one high-speed stretch (mTBI) injury. AQP4 expression was significantly increased 24 hours after mTBI. mTBI resulted in a significant increase in the cell swelling within 30 min of mTBI, which was significantly reduced in the presence of AZA. Cell death and expression of S100B was significantly reduced when AZA was added shortly before mTBI stretch. Overall, our data point to occurrence of astrocyte swelling immediately following mTBI, and AZA as a promising treatment to mitigate downstream cellular mortality.
| S-EPMC5022024 | biostudies-literature
Project description:Traumatic brain injury (TBI) is one of the leading causes of morbidity, disability and mortality across all age groups globally. Currently, only palliative treatments exist, but these are suboptimal and do little to combat the progressive damage to the brain that occurs after a TBI. However, multiple experimental treatments are currently available that target the primary and secondary biochemical and cellular changes that occur after a TBI. Some of these drugs have progressed to clinical trials and are currently being evaluated for their therapeutic benefits in TBI patients. The aim of this study was to identify which drugs are currently being evaluated in clinical trials for TBI. A search of ClinicalTrials.gov was performed on 3 December 2021 and all clinical trials that mentioned "TBI" OR "traumatic brain injury" AND "drug" were searched, revealing 362 registered trials. Of the trials, 46 were excluded due to the drug not being mentioned, leaving 138 that were completed and 116 that were withdrawn. Although the studies included 267,298 TBI patients, the average number of patients per study was 865 with a range of 5-200,000. Of the completed studies, 125 different drugs were tested in TBI patients but only 7 drugs were used in more than three studies, including amantadine, botulinum toxin A and tranexamic acid (TXA). However, previous clinical studies using these seven drugs showed variable results. The current study concludes that clinical trials in TBI have to be carefully conducted so as to reduce variability across studies, since the severity of TBI and timing of therapeutic interventions were key aspects of trial success.
| S-EPMC9138587 | biostudies-literature
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.
| S-EPMC6098411 | biostudies-literature
Project description:Traumatic brain injury (TBI) is a head injury that disrupts the normal brain structure and function. TBI has been extensively studied using various in vitro and in vivo models. Most of the studies have been done with rodent models, which may respond differently to TBI than human nerve cells. Taking advantage of the recent development of cerebral organoids (COs) derived from human induced pluripotent stem cells (iPSCs), which resemble the architecture of specific human brain regions, here, we adapted the controlled cortical impact (CCI) model to induce TBI in human COs as a novel in vitro platform. To adapt the CCI procedure into COs, we have developed a phantom brain matrix, matching the mechanical characteristics of the brain, altogether with an empty mouse skull as a platform to allow the use of the stereotactic CCI equipment on COs. After the CCI procedure, COs were histologically prepared to evaluate neurons and astrocyte populations using the microtubule-associated protein 2 (MAP2) and the glial fibrillary acidic protein (GFAP). Moreover, a marker of metabolic response, the neuron-specific enolase (NSE), and cellular death using cleaved caspase 3 were also analyzed. Our results show that human COs recapitulate the primary pathological changes of TBI, including metabolic alterations related to neuronal damage, neuronal loss, and astrogliosis. This novel approach using human COs to model TBI in vitro holds great potential and opens new alternatives for understanding brain abnormalities produced by TBI, and for the development and testing of new therapeutic approaches.
| S-EPMC8534257 | biostudies-literature
Project description:Traumatic brain injury (TBI) has been postulated to initiate a disease process that interacts with vascular dysfunction. However, the combined effects of preexisting cerebral hypoperfusion and TBI remain poorly explored. This study aimed to investigate the combined effects of bilateral carotid artery stenosis (BCAS) and mild-moderate TBI on cerebral blood flow (CBF), cognitive function, histology, and transcriptomics in Swiss-Webster mice. Male and female mice underwent BCAS using steel microcoils around the carotid arteries, followed by TBI 30 days post coil implantation. CBF, spatial learning and memory, axonal damage, and gene expression profiles were assessed. BCAS led to a ~10% reduction in CBF, while TBI caused a similar decrease. However, mice exposed to both BCAS and TBI exhibited more pronounced reductions in CBF, associated with marked spatial learning and memory deficits, particularly in males. Axonal damage in male mice was also exacerbated by the combination of BCAS and TBI. Notably, females demonstrated differential vascular and cognitive responses to BCAS and TBI, suggesting sex-specific protective mechanisms. Single nuclei RNA sequencing revealed unique, cell type-specific gene expression alterations due to BCAS, TBI, or the combination. Moreover, BCAS and TBI induced significant gene expression changes in various cell types, hinting at complex cellular interactions following vascular challenges and trauma. The cellular and molecular interplay between hypoperfusion and TBI points to intricate vascular-neuronal interactions and potential avenues for targeted interventions.
2024-08-14 | GSE241690 | GEO