Sulfonylurea Receptor 1, Transient Receptor Potential Cation Channel Subfamily M Member 4, and KIR6.2:Role in Hemorrhagic Progression of Contusion

Altres ajuts: J.M.S is supported by grants from the Department of Veterans Affairs (I01BX002889), the Department of Defense (SCI170199), the National Heart, Lung and Blood Institute (R01HL082517) and the National Institute of Neurological Disorders and Stroke (NINDS) (R01NS060801; R01NS102589; R01NS105633); V.G. is supported by a grant from NINDS (NS061934).In severe traumatic brain injury (TBI), contusions often are worsened by contusion expansion or hemorrhagic progression of contusion (HPC), which may double the original contusion volume and worsen outcome. In humans and rodents with contusion-TBI, sulfonylurea receptor 1 (SUR1) is upregulated in microvessels and astrocytes, and in rodent models, blockade of SUR1 with glibenclamide reduces HPC. SUR1 does not function by itself, but must co-assemble with either KIR6.2 or transient receptor potential cation channel subfamily M member 4 (TRPM4) to form K (SUR1-KIR6.2) or SUR1-TRPM4 channels, with the two having opposite effects on membrane potential. Both KIR6.2 and TRPM4 are reportedly upregulated in TBI, especially in astrocytes, but the identity and function of SUR1-regulated channels post-TBI is unknown. Here, we analyzed human and rat brain tissues after contusion-TBI to characterize SUR1, TRPM4, and KIR6.2 expression, and in the rat model, to examine the effects on HPC of inhibiting expression of the three subunits using intravenous antisense oligodeoxynucleotides (AS-ODN). Glial fibrillary acidic protein (GFAP) immunoreactivity was used to operationally define core versus penumbral tissues. In humans and rats, GFAP-negative core tissues contained microvessels that expressed SUR1 and TRPM4, whereas GFAP-positive penumbral tissues contained astrocytes that expressed all three subunits. Förster resonance energy transfer imaging demonstrated SUR1-TRPM4 heteromers in endothelium, and SUR1-TRPM4 and SUR1-KIR6.2 heteromers in astrocytes. In rats, glibenclamide as well as AS-ODN targeting SUR1 and TRPM4, but not KIR6.2, reduced HPC at 24 h post-TBI. Our findings demonstrate upregulation of SUR1-TRPM4 and K after contusion-TBI, identify SUR1-TRPM4 as the primary molecular mechanism that accounts for HPC, and indicate that SUR1-TRPM4 is a crucial target of glibenclamide

Pérdidas de nitrógeno y balance nitrogenado en pacientes con infarto maligno de la arteria cerebral media y sometidos a hipotermia moderada (32-33 ºC) Nitrogen losses and nitrogen balance in patients with malignant infarction of the median cerebral artery submitted to moderate hypothermia (32-33 ºC)

Objetivos: La inducción de hipotermia moderada en pacientes con infarto de la arteria cerebral media (ACM) puede ocasionar alteraciones metabólicas y nutricionales. En la actualidad se desconoce cuál es el mejor método para realizar la valoración nutricional en este grupo de población. El objetivo del presente estudio fue valorar la utilidad del balance nitrogenado en el seguimiento de pacientes con infarto de la ACM y sometidos a hipotermia moderada (32-33 ºC) mediante enfriamiento intravascular, en la Unidad de Cuidados Neurocríticos de un hospital de tercer nivel. Material y métodos: Se diseñó un estudio retrospectivo en el que se incluyeron pacientes con infarto de la ACM de los que se recogieron variables biodemográficas, clínicas, de hipotermia y nutricionales. Del mismo modo se realizó el seguimiento prospectivo de un paciente con infarto de la ACM e hipotermia inducida, recogiendo las mismas variables en distintos tiempos de su evolución clínica. Resultados: En la serie retrospectiva se incluyeron 6 pacientes con infarto de ACM sometidos a hipotermia moderada durante un periodo promedio de 12 días (intervalo 9-15). Se constataron pérdidas de nitrógeno (media 9,9 g) inferiores a las que cabría esperar en pacientes críticos durante la fase aguda. En el seguimiento prospectivo del paciente con infarto maligno de la ACM desde día 1 hasta día 22 tras la aplicación de la hipotermia se observaron, al igual que en la serie de pacientes anteriormente descrita, valores bajos de nitrógeno eliminado durante la fase de hipotermia inducida que se elevaron posteriormente cuando el paciente recuperó la normotermia. El nitrógeno eliminado promedio durante el periodo de hipotermia fue de 10,7 g y presentó una elevación hasta 27,3 g durante el periodo normotérmico (día 17). Conclusiones: Estos resultados sugieren que la supresión metabólica inducida por la hipotermia moderada es clínicamente relevante y que, por lo tanto, la determinación del balance nitrogenado no parece ser una herramienta útil en el seguimiento nutricional de este tipo de pacientes.Objectives: Induction of moderate hypothermia in patients with median cerebral artery (MCA) infarction may produce metabolic and nutritional impairments. Currently, we do not know which is the best method to carry out nutritional assessment in this population group. The aim of the present study was to assess the usefulness of nitrogen balance in the follow-up of patients with MCA submitted to moderate hypothermia (32-33 ºC) by means of intravascular cooling at the Neurocritical Patients Unit at a tertiary hospital. Material and methods: We designed a retrospective study including patients with MCA infarction of whom we gathered bio-demographical, clinical, hypothermia, and nutritional variables. Similarly, we carried out a prospective follow-up of a patient with MCA infarction and induced hypothermia, gathering the same variables at different time points of his clinical course. Results: Six patients with MCA infarction submitted to moderate hypothermia for a mean duration of 12 days (interval 9-15) were included in the retrospective series. We observed that nitrogen losses (mean 9.9 g) were lower than those previously thought for critical patients during the acute phase. During the prospective follow-up of the patient with malignant infarction of the MCA from day 1 to day 22 after the application of hypothermia, low levels of nitrogen losses were similarly observed during the phase of induced hypothermia, which increased later on when the patient recovered normothermia. The mean nitrogen expenditure during the period of hypothermia was 10.7 g and increased up to 27.3 g during the normothermia period (day 17). Conclusions: These results suggest that moderate hypothermia-induced metabolic suppression is clinically relevant and thus the determination of nitrogen balance does not seem to be a useful tool in the nutritional followup of this type of patients

Sulfonylurea Receptor 1 in Central Nervous System Injury : An Updated Review

Sulfonylurea receptor 1 (SUR1) is a member of the adenosine triphosphate (ATP)-binding cassette (ABC) protein superfamily, encoded by Abcc8, and is recognized as a key mediator of central nervous system (CNS) cellular swelling via the transient receptor potential melastatin 4 (TRPM4) channel. Discovered approximately 20 years ago, this channel is normally absent in the CNS but is transcriptionally upregulated after CNS injury. A comprehensive review on the pathophysiology and role of SUR1 in the CNS was published in 2012. Since then, the breadth and depth of understanding of the involvement of this channel in secondary injury has undergone exponential growth: SUR1-TRPM4 inhibition has been shown to decrease cerebral edema and hemorrhage progression in multiple preclinical models as well as in early clinical studies across a range of CNS diseases including ischemic stroke, traumatic brain injury, cardiac arrest, subarachnoid hemorrhage, spinal cord injury, intracerebral hemorrhage, multiple sclerosis, encephalitis, neuromalignancies, pain, liver failure, status epilepticus, retinopathies and HIV-associated neurocognitive disorder. Given these substantial developments, combined with the timeliness of ongoing clinical trials of SUR1 inhibition, now, another decade later, we review advances pertaining to SUR1-TRPM4 pathobiology in this spectrum of CNS disease-providing an overview of the journey from patch-clamp experiments to phase III trials

Role of Sulfonylurea Receptor 1 and Glibenclamide in Traumatic Brain Injury : A Review of the Evidence

Cerebral edema and contusion expansion are major determinants of morbidity and mortality after TBI. Current treatment options are reactive, suboptimal and associated with significant side effects. First discovered in models of focal cerebral ischemia, there is increasing evidence that the sulfonylurea receptor 1 (SUR1)-Transient receptor potential melastatin 4 (TRPM4) channel plays a key role in these critical secondary injury processes after TBI. Targeted SUR1-TRPM4 channel inhibition with glibenclamide has been shown to reduce edema and progression of hemorrhage, particularly in preclinical models of contusional TBI. Results from small clinical trials evaluating glibenclamide in TBI have been encouraging. A Phase-2 study evaluating the safety and efficacy of intravenous glibenclamide (BIIB093) in brain contusion is actively enrolling subjects. In this comprehensive narrative review, we summarize the molecular basis of SUR1-TRPM4 related pathology and discuss TBI-specific expression patterns, biomarker potential, genetic variation, preclinical experiments, and clinical studies evaluating the utility of treatment with glibenclamide in this diseas

Acute subdural hematoma and diffuse axonal injury in fatal road traffic accident victims: a clinico-pathological study of 15 patients Hematoma subdural agudo e lesão axonal difusa em vítimas fatais de acidente de trânsito: estudo clínico-patológico de 15 pacientes

OBJECTIVE: Although acute subdural hematoma (ASDH) and diffuse axonal injury (DAI) are commonly associated in victims of head injury due to road traffic accidents, there are only two clinico-pathological studies of this association. We report a clinical and pathological study of 15 patients with ASDH associated with DAI. METHOD: The patients were victims of road traffic accidents and were randomly chosen. The state of consciousness on hospital admission was evaluated by the Glasgow coma scale. For the identification of axons the histological sections of the brain were stained with anti-neurofilament proteins. RESULTS: Twelve of the 15 patients were admitted to hospital in a state of coma; in three patients, the level of consciousness was not evaluated, as they died before hospital admission. CONCLUSION: The poorer prognosis in patients with ASDH who lapse into coma immediately after sustaining a head injury, as described by several authors, can be explained by the almost constant association between ASDH and DAI in victims of fatal road traffic accidents.<br>OBJETIVO: Embora o hematoma subdural agudo (HSDA) e a lesão axonal difusa (LAD) estejam frequentemente associados em vítimas de trauma crânio-encefálico causado por acidentes de trânsito, há somente dois estudos clínico-patológicos sobre esta associação. Relatamos o estudo clínico-patológico de 15 pacientes com HSDA associado com LAD. MÉTODO: Os pacientes, vítimas de acidentes de trânsito, foram selecionados aleatoriamente. O estado de consciência à admissão hospitalar foi avaliado pela escala de coma de Glasgow. Para a identificação dos axônios, os cortes histológicos do cérebro foram corados com antisoro anti-proteínas do neurofilamento. RESULTADOS: Doze dos 15 pacientes foram admitidos no hospital em estado de coma; em três pacientes, o nível de consciência não foi avaliado, pois eles faleceram antes da admissão hospitalar. CONCLUSÃO: O pior prognóstico em pacientes com HSDA que apresentam coma imediatamente após serem admitidos por trauma crânio-encefálico, como descrito por vários autores, pode ser explicado pela quase que constante associação entre HSDA e LAD em vítimas fatais de acidentes de trânsito

Early management of isolated severe traumatic brain injury patients in a hospital without neurosurgical capabilities: a consensus and clinical recommendations of the World Society of Emergency Surgery (WSES).

Acknowledgements: We would like to thank WSES for the support.BACKGROUND: Severe traumatic brain-injured (TBI) patients should be primarily admitted to a hub trauma center (hospital with neurosurgical capabilities) to allow immediate delivery of appropriate care in a specialized environment. Sometimes, severe TBI patients are admitted to a spoke hospital (hospital without neurosurgical capabilities), and scarce data are available regarding the optimal management of severe isolated TBI patients who do not have immediate access to neurosurgical care. METHODS: A multidisciplinary consensus panel composed of 41 physicians selected for their established clinical and scientific expertise in the acute management of TBI patients with different specializations (anesthesia/intensive care, neurocritical care, acute care surgery, neurosurgery and neuroradiology) was established. The consensus was endorsed by the World Society of Emergency Surgery, and a modified Delphi approach was adopted. RESULTS: A total of 28 statements were proposed and discussed. Consensus was reached on 22 strong recommendations and 3 weak recommendations. In three cases, where consensus was not reached, no recommendation was provided. CONCLUSIONS: This consensus provides practical recommendations to support clinician's decision making in the management of isolated severe TBI patients in centers without neurosurgical capabilities and during transfer to a hub center

WSES consensus conference guidelines: monitoring and management of severe adult traumatic brain injury patients with polytrauma in the first 24 hours

The acute phase management of patients with severe traumatic brain injury (TBI) and polytrauma represents a major challenge. Guidelines for the care of these complex patients are lacking, and worldwide variability in clinical practice has been documented in recent studies. Consequently, the World Society of Emergency Surgery (WSES) decided to organize an international consensus conference regarding the monitoring and management of severe adult TBI polytrauma patients during the first 24 hours after injury. A modified Delphi approach was adopted, with an agreement cut-off of 70%. Forty experts in this field (emergency surgeons, neurosurgeons, and intensivists) participated in the online consensus process. Sixteen recommendations were generated, with the aim of promoting rational care in this difficult setting