Endotypes and the Path to Precision in Moderate and Severe Traumatic Brain Injury

Azad, Tej D.; Shah, P.; Kim, Han B; Stevens, Robert D.

doi:10.1007/s12028-022-01475-6

Cited by 14 publications

(19 citation statements)

References 69 publications

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“…1(p301) Galileo Galilei Trauma endotypes (TEs) characterize patients based on dynamic changes in immune and inflammatory biomarkers after injury. 2,3 Most frequently cited endotypes are hyperinflammatory and hypoinflammatory subtypes. Previous research in trauma, sepsis, and acute respiratory distress syndrome (ARDS) has demonstrated that different endotypes have distinct responses to therapies impacting outcomes.…”

Section: Invited Commentarymentioning

confidence: 99%

“…Previous research in trauma, sepsis, and acute respiratory distress syndrome (ARDS) has demonstrated that different endotypes have distinct responses to therapies impacting outcomes. [2][3][4] In this interesting analysis, Thau and colleagues 5 have applied the concept of TEs to the Pragmatic, Randomized Optimal Platelet and Plasma Ratio (PROPPR) trial study population. The original PROPPR trial evaluated the impact of 2 different transfusion strategies of plasma, platelets, and packed red blood cells (PRBCs) in trauma patients with hemorrhaging.…”

Section: Invited Commentarymentioning

confidence: 99%

“…By applying endotypes to assess for a differential response to transfusion, the authors identified that the TE-2 group, which had lower concentrations of all biomarkers, had improved survival with the 1:1:1 transfusion ratio vs the 1:1:2 ratio. This is a comparable result to other studies evaluating ARDS that initially demonstrated similar outcomes between groups based on conventional study characteristics but were able to establish differences once assessing outcomes based on endotypes . These findings prompt us to ask what other features outside of traditional phenotypes should be considered when evaluating groups in large studies.…”

mentioning

confidence: 99%

“…Trauma endotypes (TEs) characterize patients based on dynamic changes in immune and inflammatory biomarkers after injury . Most frequently cited endotypes are hyperinflammatory and hypoinflammatory subtypes.…”

mentioning

confidence: 99%

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Optimizing Hemostatic Resuscitation in Trauma—Will Endotyping Be the Key to the “Proper” Ratio?

Patel

Martin

2023

JAMA Surg

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Section: Invited Commentarymentioning

confidence: 99%

Section: Invited Commentarymentioning

confidence: 99%

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confidence: 99%

mentioning

confidence: 99%

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Optimizing Hemostatic Resuscitation in Trauma—Will Endotyping Be the Key to the “Proper” Ratio?

Patel

Martin

2023

JAMA Surg

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“…Two articles in this special issue seek to leverage data to dissect endotypes, which are patient subgroups that share biologic characteristics and might respond in a more uniform way. Azad et al [5] propose a data-driven endotype approach for traumatic brain injury. The PREcision Care in cardiac arrest: Influence of Cooling duration on Efficacy in Cardiac Arrest Patients (PRECICECAP) investigators apply a similar data-driven philosophy to cardiac arrest [6] to "better define patterns of injury and tailor acute interventions" as a potential way to improve patient outcomes.…”

mentioning

confidence: 99%

Navigating the Ocean of Big Data in Neurocritical Care

Dhar

Meyfroidt

2022

Neurocrit Care

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Artificial intelligence (AI) will inevitably infiltrate and increasingly influence clinical practice and research in neurocritical care. The question is no longer whether or even when this will happen but how we respond to the opportunities and threats of exploring this terra incognita: some clinicians may watch anxiously from the shore as the AI armada sets sail for uncharted territory, whereas those who are more adventurous have elected to embark as "captains of big data" and determine the trajectory and destination of this scientific journey. Navigating through this still murky ocean of big data requires knowledge of evolving statistical and data analytic techniques that look to many like black magic. In reality, there is no mystical conjuring involved: machine learning techniques derive rules and reveal patterns in data by leveraging statistical analyses at an enormous scale and by combining variables in nonlinear and multidimensional ways. Just as with other statistical approaches, they cannot predict the future or make definitive causal inferences. It is imperative that physicians possess at least a modest understanding of the possibilities and limitations of AI to thrive in this technological future. This special issue of Neurocritical Care aims to guide the reader through this fascinating frontier of research. We invited several experts to review, debate, and provide perspectives on key aspects of these techniques and their potential to impact our field. We also include several original research submissions that harness big data and AI approaches to advance our understanding of common and vexing challenges in neurocritical care.

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

Jha

Simard

2023

Neurotherapeutics

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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.

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Endotypes and the Path to Precision in Moderate and Severe Traumatic Brain Injury

Cited by 14 publications

References 69 publications

Optimizing Hemostatic Resuscitation in Trauma—Will Endotyping Be the Key to the “Proper” Ratio?

Optimizing Hemostatic Resuscitation in Trauma—Will Endotyping Be the Key to the “Proper” Ratio?

Navigating the Ocean of Big Data in Neurocritical Care

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

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