Glibenclamide for Brain Contusions: Contextualizing a Promising Clinical Trial Design that Leverages an Imaging-Based TBI Endotype.

TBI heterogeneity is recognized as a major impediment to successful translation of therapies that could improve morbidity and mortality after injury. This heterogeneity exists on multiple levels including primary injury, secondary injury/host-response, and recovery. One widely accepted type of primary-injury related heterogeneity is pathoanatomic-the intracranial compartment that is predominantly affected, which can include any combination of subdural, subarachnoid, intraparenchymal, diffuse axonal, intraventricular and epidural hemorrhages. Intraparenchymal contusions carry the highest risk for progression. Contusion expansion is one of the most important drivers of death and disability after TBI. Over the past decade, there has been increasing evidence of the role of the sulfonylurea-receptor 1-transient receptor potential melastatin 4 (SUR1-TRPM4) channel in secondary injury after TBI, including progression of both cerebral edema and intraparenchymal hemorrhage. Inhibition of SUR1-TRPM4 with glibenclamide has shown promising results in preclinical models of contusional TBI with benefits against cerebral edema, secondary hemorrhage progression of the contusion, and improved functional outcome. Early-stage human research supports the key role of this pathway in contusion expansion and suggests a benefit with glibenclamide inhibition. ASTRAL is an ongoing international multi-center double blind multidose placebo-controlled phase-II clinical trial evaluating the safety and efficacy of an intravenous formulation of glibenclamide (BIIB093). ASTRAL is a unique and innovative study that addresses TBI heterogeneity by limiting enrollment to patients with the TBI pathoanatomic endotype of brain contusion and using contusion-expansion (a mechanistically linked secondary injury) as its primary outcome. Both criteria are consistent with the strong supporting preclinical and molecular data. In this narrative review, we contextualize the development and design of ASTRAL, including the need to address TBI heterogeneity, the scientific rationale underlying the focus on brain contusions and contusion-expansion, and the preclinical and clinical data supporting benefit of SUR1-TRPM4 inhibition in this specific endotype. Within this framework, we summarize the current study design of ASTRAL which is sponsored by Biogen and actively enrolling with a goal of 160 participants.

Precision Effects of Glibenclamide on MRI Endophenotypes in Clinically Relevant Murine Traumatic Brain Injury.

OBJECTIVES: Addressing traumatic brain injury (TBI) heterogeneity is increasingly recognized as essential for therapy translation given the long history of failed clinical trials. We evaluated differential effects of a promising treatment (glibenclamide) based on dose, TBI type (patient selection), and imaging endophenotype (outcome selection). Our goal to inform TBI precision medicine is contextually timely given ongoing phase 2/planned phase 3 trials of glibenclamide in brain contusion. DESIGN: Blinded randomized controlled preclinical trial of glibenclamide on MRI endophenotypes in two established severe TBI models: controlled cortical impact (CCI, isolated brain contusion) and CCI+hemorrhagic shock (HS, clinically common second insult). SETTING: Preclinical laboratory. SUBJECTS: Adult male C57BL/6J mice (n = 54). INTERVENTIONS: Mice were randomized to naïve, CCI±HS with vehicle/low-dose (20 µg/kg)/high-dose glibenclamide (10 µg/mouse). Seven-day subcutaneous infusions (0.4 µg/hr) were continued. MEASUREMENTS AND MAIN RESULTS: Serial MRI (3 hr, 6 hr, 24 hr, and 7 d) measured hematoma and edema volumes, T2 relaxation (vasogenic edema), apparent diffusion coefficient (ADC, cellular/cytotoxic edema), and 7-day T1-post gadolinium values (blood-brain-barrier [BBB] integrity). Linear mixed models assessed temporal changes. Marked heterogeneity was observed between CCI versus CCI+HS in terms of different MRI edema endophenotypes generated (all p < 0.05). Glibenclamide had variable impact. High-dose glibenclamide reduced hematoma volume ~60% after CCI (p = 0.0001) and ~48% after CCI+HS (p = 4.1 × 10-6) versus vehicle. Antiedema benefits were primarily in CCI: high-dose glibenclamide normalized several MRI endophenotypes in ipsilateral cortex (all p < 0.05, hematoma volume, T2, ADC, and T1-post contrast). Acute effects (3 hr) were specific to hematoma (p = 0.001) and cytotoxic edema reduction (p = 0.0045). High-dose glibenclamide reduced hematoma volume after TBI with concomitant HS, but antiedema effects were not robust. Low-dose glibenclamide was not beneficial. CONCLUSIONS: High-dose glibenclamide benefitted hematoma volume, vasogenic edema, cytotoxic edema, and BBB integrity after isolated brain contusion. Hematoma and cytotoxic edema effects were acute; longer treatment windows may be possible for vasogenic edema. Our findings provide new insights to inform interpretation of ongoing trials as well as precision design (dose, sample size estimation, patient selection, outcome selection, and Bayesian analysis) of future TBI trials of glibenclamide.

Dexamethasone for the treatment of traumatic brain injured patients with brain contusions and pericontusional edema: Study protocol for a prospective, randomized and double blind trial.

BACKGROUND: Traumatic brain injury (TBI) constitutes a leading cause of death and disability. Patients with TBI and cerebral contusions developing pericontusional edema are occasionally given dexamethasone on the belief that this edema is similar to that of tumors, in which the beneficial effect of dexamethasone has been demonstrated. METHODS: The DEXCON TBI trial is a multicenter, pragmatic, randomized, triple-blind, placebo controlled trial to quantify the effects of dexamethasone on the prognosis of TBI patients with brain contusions and pericontusional edema. Adult patients who fulfill the elegibility criteria will be randomized to dexamethasone/placebo in a short and descending course: 4 mg/6 h (2 days); 4 mg/8 hours (2 days); 2 mg/6 hours (2 days); 2 mg/8 hours (2 days); 1 mg/8 hours (2 days); 1 mg/12 hours (2 days). The primary outcome is the Glasgow Scale Outcome Extended (GOSE) performed 1 month and 6 months after TBI. Secondary outcomes are: number of episodes of neurological deterioration; symptoms associated with TBI; adverse events; volume of pericontusional edema before and after 12 days of treatment; results of the neuropsychological tests one month and 6 months after TBI. The main analysis will be on an "intention-to-treat" basis. Logistic regression will estimate the effect of dexamethasone/placebo on GOSE at one month and at 6 months, dichotomized in unfavorable outcome (GOSE 1-6) and favorable outcome (GOSE 7-8). Efficacy will also be analyzed using the 'sliding dichotomy'. An interim and safety analysis will be performed including patients recruited during the first year to calculate the conditional power. A study with 600 patients would have 80% power (2 sided alpha = 5%) to detect a 12% absolute increase (from 50% to 62%) in good recovery. DISCUSSION: This is a confirmative trial to elucidate the therapeutic efficacy of dexamethasone in a very specific group of TBI patients: patients with brain contusions and pericontusional edema. This trial could become an important milestone for TBI patients as nowadays there is no effective treatment in this type of patients. TRIAL REGISTRATION: eudraCT: 2019-004038-41; Clinical Trials.gov: NCT04303065.

Early tranexamic acid in traumatic brain injury: Evidence for an effective therapy.

The guidelines for management of traumatic brain injury (TBI) are based largely on measures to maintain an optimum internal milieu for prevention of secondary brain injury and enhancing recovery. One of the most common reasons for worsening outcomes following TBI is expanding intracranial haematoma which is compounded by the fibrinolytic physiology that follows TBI. Tranexamic acid (TXA) has a time tested role in preventing poor outcomes linked to excessive haemorrhage in trauma patients. Historically, patients with isolated head trauma were excluded from TXA use due to a theoretical increased risk of thrombosis. Recent evidence that redefines the beneficial role of early TXA administration in preventing mortality amongst patients with TBI is now at hand and offers a real prospect of a pharmacological intervention that would be adopted as a recommendation based on Class l evidence.

Intravenous Tranexamic Acid for Brain Contusion with Intraparenchymal Hemorrhage: Randomized, Double-Blind, Placebo-Controlled Trial.

INTRODUCTION: Controlling of secondary traumatic brain injuries (TBI) is necessary due to its salient effect on the improvement of patients with TBI and the final outcomes within early hours of trauma onset. This study aims to investigate the effect of intravenous tranexamic acid (TAX) administration on decreased hemorrhage during surgery. METHODS: This double-blind, randomized, and placebo-controlled trial was conducted on patients referring to the emergency department (ED) with IPH due to brain contusion within 8 h of injury onset. The patients were evaluated by receiving TXA and 0.9% normal saline as a placebo. The following evaluation and estimations were performed: intracranial hemorrhage volume after surgery using brain CT-scan; hemoglobin (Hb) volume before, immediately after, and six hours after surgery; and the severity of TBI based on Glasgow Coma Score (GCS). RESULTS: 40 patients with 55.02 ± 18.64 years old diagnosed with a contusion and intraparenchymal hemorrhage. Although the (Mean ± SD) hemorrhage during surgery in patients receiving TXA (784.21 ± 304.162) was lower than the placebo group (805.26 ± 300.876), no significant difference was observed between two groups (P=0.83). The (Mean ± SD) Hb volume reduction immediately during surgery (0.07 ± 0.001 and 0.23 ± 0.02) and six hours after surgery (0.04 ± 0.008 and 0.12 ± 0.006) was also lower in TXA group but had no significant difference (P = 0.89 and P = 0.97, respectively). CONCLUSION: Using TXA may reduce the hemorrhage in patients with TBI, but this effect, as in this study, was not statistically significant and it is suggested that a clinical trial with a larger population is employed for further investigation.

Treating head injury using a novel vasopressin 1a receptor antagonist.

Arginine vasopressin (AVP) is a chemical signal in the brain that influences cerebral vascular resistance and brain water permeability. Increases in AVP contribute to the pathophysiology of brain edema following traumatic brain injury (TBI). These effects are mediated through AVP V1a receptors that are expressed in cortical and subcortical brain areas. This exploratory study characterizes the effects of a novel, V1a receptor antagonist, AVN576, on behavioral and magnetic resonance imaging (MRI) measures after severe TBI. Male Sprague Dawley rats were impacted twice producing contusions in the forebrain, putative cerebral edema, and cognitive deficits. Rats were treated with AVN576 after initial impact for 5 days and then tested for changes in cognition. MRI was used to assess brain injury, enlargement of the ventricles, and resting state functional connectivity. Vehicle treated rats had significant deficits in learning and memory, enlarged ventricular volumes, and hypoconnectivity in hippocampal circuitry. AVN576 treatment eliminated the enlargement of the lateral ventricles and deficits in cognitive function while increasing connectivity in hippocampal circuitry. These data corroborate the extensive literature that drugs selectively targeting the AVP V1a receptor could be used to treat TBI in the clinic.

The p53 inactivators pifithrin-µ and pifithrin-α mitigate TBI-induced neuronal damage through regulation of oxidative stress, neuroinflammation, autophagy and mitophagy.

Traumatic brain injury (TBI) is one of the most common causes of death and disability worldwide. We investigated whether inhibition of p53 using pifithrin (PFT)-α or PFT-µ provides neuroprotective effects via p53 transcriptional dependent or -independent mechanisms, respectively. Sprague Dawley rats were subjected to controlled cortical impact TBI followed by the administration of PFTα or PFT-µ (2 mg/kg, i.v.) at 5 h after TBI. Brain contusion volume, as well as sensory and motor functions were evaluated at 24 h after TBI. TBI-induced impairments were mitigated by both PFT-α and PFT-µ. Fluoro-Jade C staining was used to label degenerating neurons within the TBI-induced cortical contusion region that, together with Annexin V positive neurons, were reduced by PFT-µ. Double immunofluorescence staining similarly demonstrated that PFT-µ significantly increased HO-1 positive neurons and mRNA expression in the cortical contusion region as well as decreased numbers of 4-hydroxynonenal (4HNE)-positive cells. Levels of mRNA encoding for p53, autophagy, mitophagy, anti-oxidant, anti-inflammatory related genes and proteins were measured by RT-qPCR and immunohistochemical staining, respectively. PFT-α, but not PFT-µ, significantly lowered p53 mRNA expression. Both PFT-α and PFT-µ lowered TBI-induced pro-inflammatory cytokines (IL-1ß and IL-6) mRNA levels as well as TBI-induced autophagic marker localization (LC3 and p62). Finally, treatment with PFT-µ mitigated TBI-induced declines in mRNA levels of PINK-1 and SOD2. Our data suggest that both PFT-µ and PFT-α provide neuroprotective actions through regulation of oxidative stress, neuroinflammation, autophagy, and mitophagy mechanisms, and that PFT-µ, in particular, holds promise as a TBI treatment strategy.

(-)-Phenserine Ameliorates Contusion Volume, Neuroinflammation, and Behavioral Impairments Induced by Traumatic Brain Injury in Mice.

Traumatic brain injury (TBI), a major cause of mortality and morbidity, affects 10 million people worldwide, with limited treatment options. We have previously shown that (-)-phenserine (Phen), an acetylcholinesterase inhibitor originally designed and tested in clinical phase III trials for Alzheimer's disease, can reduce neurodegeneration after TBI and reduce cognitive impairments induced by mild TBI. In this study, we used a mouse model of moderate to severe TBI by controlled cortical impact to assess the effects of Phen on post-trauma histochemical and behavioral changes. Animals were treated with Phen (2.5 mg/kg, IP, BID) for 5 days started on the day of injury and the effects were evaluated by behavioral and histological examinations at 1 and 2 weeks after injury. Phen significantly attenuated TBI-induced contusion volume, enlargement of the lateral ventricle, and behavioral impairments in motor asymmetry, sensorimotor functions, motor coordination, and balance functions. The morphology of microglia was shifted to an active from a resting form after TBI, and Phen dramatically reduced the ratio of activated to resting microglia, suggesting that Phen also mitigates neuroinflammation after TBI. While Phen has potent anti-acetylcholinesterase activity, its (+) isomer Posiphen shares many neuroprotective properties but is almost completely devoid of anti-acetylcholinesterase activity. We evaluated Posiphen at a similar dose to Phen and found similar mitigation in lateral ventricular size increase, motor asymmetry, motor coordination, and balance function, suggesting the improvement of these histological and behavioral tests by Phen treatment occur via pathways other than anti-acetylcholinesterase inhibition. However, the reduction of lesion size and improvement of sensorimotor function by Posiphen were much smaller than with equivalent doses of Phen. Taken together, these results show that post-injury treatment with Phen over 5 days significantly ameliorates severity of TBI. These data suggest a potential development of this compound for clinical use in TBI therapy.

Improving Survival with Tranexamic Acid in Cerebral Contusions or Traumatic Subarachnoid Hemorrhage: Univariate and Multivariate Analysis of Independent Factors Associated with Lower Mortality.

BACKGROUND: Fall with head injury is a pervasive challenge, especially in the aging population. Contributing factors for mortality include the development of cerebral contusions and delayed traumatic intracerebral hematoma. Currently, there is no established specific treatment for these conditions. OBJECT: This study aimed to investigate the impact of independent factors on the mortality rate of traumatic brain injury with contusions or traumatic subarachnoid hemorrhage. METHODS: Data were collected from consecutive patients admitted for cerebral contusions or traumatic subarachnoid hemorrhage at an academic trauma center from 2010 to 2016. The primary outcome was the 30-day mortality rate. Independent factors for analysis included patient factors and treatment modalities. Univariate and multivariate analyses were conducted to identify independent factors related to mortality. Secondary outcomes included thromboembolic complication rates associated with the use of tranexamic acid. RESULTS: In total, 651 consecutive patients were identified. For the patient factors, low Glasgow Coma Scale on admission, history of renal impairment, and use of warfarin were identified as independent factors associated with higher mortality from univariate and multivariate analyses. For the treatment modalities, univariate analysis identified tranexamic acid as an independent factor associated with lower mortality (P = 0.021). Thromboembolic events were comparable in patients with or without tranexamic acid. CONCLUSION: Tranexamic acid was identified by univariate analysis as an independent factor associated with lower mortality in cerebral contusions or traumatic subarachnoid hemorrhage. Further prospective studies are needed to validate this finding.

L-Carnitine and extendin-4 improve outcomes following moderate brain contusion injury.

There is a need for pharmaceutical agents that can reduce neuronal loss and improve functional deficits following traumatic brain injury (TBI). Previous research suggests that oxidative stress and mitochondrial dysfunction play a major role in neuronal damage after TBI. Therefore, this study aimed to investigate two drugs known to have antioxidant effects, L-carnitine and exendin-4, in rats with moderate contusive TBI. L-carnitine (1.5 mM in drinking water) or exendin-4 (15 µg/kg/day, ip) were given immediately after the injury for 2 weeks. Neurological function and brain histology were examined (24 h and 6 weeks post injury). The rats with TBI showed slight sensory, motor and memory functional deficits at 24 h, but recovered by 6 weeks. Both treatments improved sensory and motor functions at 24 h, while only exendin-4 improved memory. Both treatments reduced cortical contusion at 24 h and 6 weeks, however neither affected gliosis and inflammatory cell activation. Oxidative stress was alleviated and mitochondrial reactive oxygen species was reduced by both treatments, however only mitochondrial functional marker protein transporter translocase of outer membrane 20 was increased at 24 h post injury. In conclusion, L-carnitine and exendin-4 treatments immediately after TBI can improve neurological functional outcome and tissue integrity by reducing oxidative stress.

Effects of atorvastatin on brain contusion volume and functional outcome of patients with moderate and severe traumatic brain injury; a randomized double-blind placebo-controlled clinical trial.

The aim of the current study was to investigate the effects of atorvastatin on brain contusion volume and functional outcome of patients with moderate and severe traumatic brain injury (TBI). The study was conducted as a randomized clinical trial during a 16-month period from May 2015 and August 2016 in a level I trauma center in Shiraz, Southern Iran. We included 65 patients with moderate (GCS: 9-13) to severe (GCS: 5-8) TBI who had brain contusions of less than 30cc volume. We excluded those who required surgical intervention. Patients were randomly assigned to receive daily 20mg atorvastatin for 10days (n=21) or placebo in the same dosage (n=23). The brain contusion volumetry was performed on days 0, 3 and 7 utilizing spiral thin-cut brain CT-Scan (1-mm thickness). The outcome measured included modified Rankin scale (MRS), Glasgow Outcome Scale (GOS) and Disability rating Scale (DRS) which were all evaluated 3months post-injury. There was no significant difference between two study group regarding the baseline, 3rd day and 7th day of the contusion volume and the rate of contusion expansion. However, functional outcome scales of GOS, MRS and DRS at 3-months post-injury were significantly better in atorvastatin arm of the study compared to placebo (p values of 0.043, 0.039 and 0.030 respectively). Even though atorvastatin was not found to be more effective than placebo in reducing contusion expansion rate, it was associated with improved functional outcomes at 3-months following moderate to severe TBI.

Isoflurane-Associated Mydriasis Mimicking Blown Pupils in a Patient Treated in a Neurointensive Care Unit.

We report a misinterpretation of bilateral mydriasis as blown pupils related to elevated intracranial pressure (ICP) under volatile sedation with isoflurane (Anesthetic Conserving Device [AnaConDa], Hudson RCI, Uppland Vasby, Sweden) in a 59-year-old patient with a severe traumatic brain injury with frontal contusion. The patient showed bilateral mydriasis and a missing light reflex 8 hours after changing sedation from intravenous treatment with midazolam and esketamine to volatile administration of isoflurane. Because cranial computed tomography ruled out signs of cerebral herniation, we assumed the bilateral mydriasis was caused by isoflurane and reduced the isoflurane supply. Upon this reduction the mydriasis regressed, suggesting the observed mydriasis was related to an overdose of isoflurane. Intensivists should be aware of the reported phenomenon to avoid unnecessary diagnostic investigations that might harm the patient. We recommend careful control of the isoflurane dose when fixed and dilated pupils appear in patients without other signs of elevated ICP.