BACKGROUND AND OBJECTIVES: Spreading depolarizations (SDs) are a pathological mechanism that mediates lesion development in cerebral gray matter. They occur in ∼60% of patients with severe traumatic brain injury (TBI), often in recurring and progressive patterns from days 0 to 10 after injury, and are associated with worse outcomes. However, there are no protocols or trials suggesting how SD monitoring might be incorporated into clinical management. The objective of this protocol is to determine the feasibility and efficacy of implementing a treatment protocol for intensive care of patients with severe TBI that is guided by electrocorticographic monitoring of SDs. METHODS: Patients who undergo surgery for severe TBI with placement of a subdural electrode strip will be eligible for enrollment. Those who exhibit SDs on electrocorticography during intensive care will be randomized 1:1 to either (1) standard care that is blinded to the further course of SDs or (2) a tiered intervention protocol based on efficacy to suppress further SDs. Interventions aim to block the triggering and propagation of SDs and include adjusted targets for management of blood pressure, CO 2 , temperature, and glucose, as well as ketamine pharmacotherapy up to 4 mg/kg/ hour. Interventions will be escalated and de-escalated depending on the course of SD pathology. EXPECTED OUTCOMES: We expect to demonstrate that electrocorticographic monitoring of SDs can be used as a real- time diagnostic in intensive care that leads to meaningful changes in patient management and a reduction in secondary injury, as compared with standard care, without increasing medical complications or adverse events. DISCUSSION: This trial holds potential for personalization of intensive care management by tailoring therapies based on monitoring and confirmation of the targeted neuronal mechanism of SD. Results are expected to validate the concept of this approach, inform refinement of the treatment protocol, and lead to larger-scale trials.
A modern understanding of how cerebral cortical lesions develop after acute brain injury is based on Aristides Leão’s historic discoveries of spreading depression and asphyxial/anoxic depolarization. Treated as separate entities for decades, we now appreciate that these events define a continuum of spreading mass depolarizations, a concept that is central to understanding their pathologic effects. Within minutes of acute severe ischemia, the onset of persistent depolarization triggers the breakdown of ion homeostasis and development of cytotoxic edema. These persistent changes are diagnosed as diffusion restriction in magnetic resonance imaging and define the ischemic core. In delayed lesion growth, transient spreading depolarizations arise spontaneously in the ischemic penumbra and induce further persistent depolarization and excitotoxic damage, progressively expanding the ischemic core. The causal role of these waves in lesion development has been proven by real-time monitoring of electrophysiology, blood flow, and cytotoxic edema. The spreading depolarization continuum further applies to other models of acute cortical lesions, suggesting that it is a universal principle of cortical lesion development. These pathophysiologic concepts establish a working hypothesis for translation to human disease, where complex patterns of depolarizations are observed in acute brain injury and appear to mediate and signal ongoing secondary damage.
Objectives: Survivors of moderate and severe traumatic brain injury (TBI) require substantial care, much of which is ultimately provided by friends and family. We sought to describe the unmet needs of informal caregivers. Design: Qualitative, semistructured interviews with informal caregivers of moderate and severe TBI survivors were conducted 72 hours, 1 month, 3 months, and 6 months after injury. Setting: Intensive care unit of a level 1 trauma center. Participants: Informal caregivers were friends or family who planned to provide care for the patient. Patients were 18 years or older with a moderate to severe TBI, and not expected to imminently die of their injuries. Measurements and Main Results: Eighteen patient-caregiver dyads were enrolled. Fifty-three interviews with caregivers were completed and analyzed over the course of 6 months. Three themes were identified in the qualitative analysis: caregiver burden, caregiver health-related quality of life, and caregiver needs for information and support. Conclusions: This study provides new information about the experience of informal caregivers during the 6 months after their friend or family member survived a moderate to severe TBI. Interventions to promote caregiving may be a substantial opportunity to improve patient-centered outcomes following TBI.
Abstract Disorders of consciousness are neurological conditions characterized by impaired arousal and awareness of self and environment. Behavioural responses are absent or are present but fluctuate. Disorders of consciousness are commonly encountered as a consequence of both acute and chronic brain injuries, yet reliable epidemiological estimates would require inclusive, operational definitions of the concept, as well as wider knowledge dissemination among involved professionals. Whereas several manifestations have been described, including coma, vegetative state/unresponsive wakefulness syndrome and minimally conscious state, a comprehensive neurobiological definition for disorders of consciousness is still lacking. The scientific literature is primarily observational, and studies-specific aetiologies lead to disorders of consciousness. Despite advances in these disease-related forms, there remains uncertainty about whether disorders of consciousness are a disease-agnostic unitary entity with a common mechanism, prognosis or treatment response paradigm. Our knowledge of disorders of consciousness has also been hampered by heterogeneity of study designs, variables, and outcomes, leading to results that are not comparable for evidence synthesis. The different backgrounds of professionals caring for patients with disorders of consciousness and the different goals at different stages of care could partly explain this variability. The Prospective Studies working group of the Neurocritical Care Society Curing Coma Campaign was established to create a platform for observational studies and future clinical trials on disorders of consciousness and coma across the continuum of care. In this narrative review, the author panel presents limitations of prior observational clinical research and outlines practical considerations for future investigations. A narrative review format was selected to ensure that the full breadth of study design considerations could be addressed and to facilitate a future consensus-based statement (e.g. via a modified Delphi) and series of recommendations. The panel convened weekly online meetings from October 2021 to December 2022. Research considerations addressed the nosographic status of disorders of consciousness, case ascertainment and verification, selection of dependent variables, choice of covariates and measurement and analysis of outcomes and covariates, aiming to promote more homogeneous designs and practices in future observational studies. The goal of this review is to inform a broad community of professionals with different backgrounds and clinical interests to address the methodological challenges imposed by the transition of care from acute to chronic stages and to streamline data gathering for patients with disorders of consciousness. A coordinated effort will be a key to allow reliable observational data synthesis and epidemiological estimates and ultimately inform condition-modifying clinical trials.
Abstract Post–intensive care syndrome (PICS) refers to unintended consequences of critical care that manifest as new or worsening impairments in physical functioning, cognitive ability, or mental health. As intensive care unit (ICU) survival continues to improve, PICS is becoming increasingly recognized as a public health problem. Studies that focus on PICS have typically excluded patients with acute brain injuries and chronic neurodegenerative problems. However, patients who require neurocritical care undoubtedly suffer from impairments that overlap substantially with those encompassed by PICS. A major challenge is to distinguish between impairments related to brain injury and those that occur as a consequence of critical care. The general principles for the prevention and management of PICS and multidomain impairments in patients with moderate and severe neurological injuries are similar including the ICU liberation bundle, multidisciplinary team-based care throughout the continuum of care, and increasing awareness regarding the challenges of critical care survivorship among patients, families, and multidisciplinary team members. An extension of this concept, PICS-Family (PICS-F) refers to the mental health consequences of the intensive care experience for families and loved ones of ICU survivors. A dyadic approach to ICU survivorship with an emphasis on recognizing families and caregivers that may be at risk of developing PICS-F after neurocritical care illness can help improve outcomes for ICU survivors. In this review, we will summarize our current understanding of PICS and PICS-F, emerging literature on PICS in severe acute brain injury, strategies for preventing and treating PICS, and share our recommendations for future directions.
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