RESUMEN
BACKGROUND: We lack specific treatments for traumatic brain injury (TBI), which remains the leading cause of trauma-related morbidity and mortality. Treatment with valproic acid (VPA) improves outcomes in models of severe TBI with concurrent hemorrhage. However, it is unknown if VPA will have similar benefits after isolated nonlethal TBI, which is the more common clinical scenario. The goal of this study was to evaluate the effect of VPA treatment in a preclinical isolated TBI swine model on neurologic outcomes and brain lesion size and to perform detailed pharmacokinetic analyses for a future clinical trial. METHODS: Yorkshire swine (n = 10; 5/cohort) were subjected to TBI (8-mm controlled cortical impact). An hour later, we randomized them to receive VPA (150 mg/kg) or saline placebo (control). Neuroseverity scores were assessed daily (0 [normal] to 36 [comatose]), brain lesion size was measured on postinjury 3, and serial blood samples were collected for pharmacokinetic studies. RESULTS: Physiologic parameters and laboratory values were similar in both groups. Valproic acid-treated animals demonstrated significantly better neuroseverity scores on postinjury 1 (control, 9.2 ± 4.4; VPA, 0 ± 0; p = 0.001). Valproic acid-treated animals had significantly smaller brain lesion sizes (mean volume in microliter: control, 3,130 ± 2,166; VPA, 764 ± 208; p = 0.02). Pharmacokinetic data confirmed adequate plasma and tissue levels of VPA. CONCLUSION: In this clinically relevant model of isolated TBI, a single dose of VPA attenuates neurological impairment and decreases brain lesion size.
Asunto(s)
Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Encéfalo/efectos de los fármacos , Resucitación/métodos , Ácido Valproico/administración & dosificación , Animales , Encéfalo/patología , Lesiones Traumáticas del Encéfalo/patología , Modelos Animales de Enfermedad , Femenino , Humanos , Sus scrofaRESUMEN
BACKGROUND: Hemorrhage is a leading cause of mortality in trauma. Resuscitative endovascular balloon occlusion of the aorta (REBOA) can control hemorrhage, but distal ischemia, subsequent reperfusion injury, and the need for frequent balloon titration remain problems. Improved device design can allow for partial REBOA (pREBOA) that may provide hemorrhage control while also perfusing distally without need for significant provider titration. METHODS: Female Yorkshire swine (N = 10) were subjected to 40% hemorrhagic shock for 1 hour (mean arterial pressure [MAP], 28-32 mm Hg). Animals were then randomized to either complete aortic occlusion (ER-REBOA) or partial occlusion (novel pREBOA-PRO) without frequent provider titration or distal MAP targets. Detection of a trace distal waveform determined partial occlusion in the pREBOA-PRO arm. After 2 hours of zone 1 occlusion, the hemorrhaged whole blood was returned. After 50% autotransfusion, the balloon was deflated over a 10-minute period. Following transfusion, the animals were survived for 2 hours while receiving resuscitation based on objective targets: lactated Ringer's fluid boluses (goal central venous pressure, ≥ 6 mm Hg), a norepinephrine infusion (goal MAP, 55-60 mm Hg), and acid-base correction (goal pH, >7.2). Hemodynamic variables, arterial lactate, lactate dehydrogenase, aspartate aminotransferase, and creatinine levels were measured. RESULTS: All animals survived throughout the experiment, with similar increase in proximal MAPs in both groups. Animals that underwent partial occlusion had slightly higher distal MAPs. At the end of the experiment, the partial occlusion group had lower end levels of serum lactate (p = 0.006), lactate dehydrogenase (p = 0.0004) and aspartate aminotransferase (p = 0.004). Animals that underwent partial occlusion required less norepinephrine (p = 0.002), less bicarbonate administration (p = 0.006), and less fluid resuscitation (p = 0.042). CONCLUSION: Improved design for pREBOA can decrease the degree of distal ischemia and reperfusion injury compared with complete aortic occlusion, while providing a similar increase in proximal MAPs. This can allow pREBOA zone-1 deployment for longer periods without the need for significant balloon titration.
Asunto(s)
Aorta , Oclusión con Balón/instrumentación , Procedimientos Endovasculares/instrumentación , Daño por Reperfusión/prevención & control , Resucitación/instrumentación , Choque Hemorrágico/terapia , Animales , Presión Arterial , Oclusión con Balón/efectos adversos , Oclusión con Balón/métodos , Modelos Animales de Enfermedad , Procedimientos Endovasculares/efectos adversos , Procedimientos Endovasculares/métodos , Femenino , Daño por Reperfusión/etiología , Resucitación/efectos adversos , Resucitación/métodos , PorcinosRESUMEN
BACKGROUND: Traumatic brain injury (TBI) and hemorrhage remain the leading causes of death after trauma. We have previously shown that a dose of valproic acid (VPA) at (150 mg/kg) can decrease brain lesion size and hasten neurologic recovery. The current Food and Drug Administration-approved dose of VPA is 60 mg/kg. We evaluate neurologic outcomes and brain lesion size of a single dose of VPA at a level currently within Food and Drug Administration-approved dose in swine subjected to TBI and hemorrhagic shock. METHODS: Swine (n = 5/group) were subjected to TBI and 40% blood volume hemorrhage. Animals remained in shock for 2 hours before randomization to normal saline (NS) resuscitation alone (control), NS-VPA 150 mg/kg (VPA 150), or NS-VPA 50 mg/kg (VPA 50). Neurologic severity scores (range, 0-32) were assessed daily for 14 days, and brain lesion size was measured via magnetic resonance imaging on postinjury day (PID) 3. RESULTS: Shock severity and laboratory values were similar in all groups. Valproic acid-treated animals demonstrated significantly less neurologic impairment on PID 1 and returned to baseline faster (PID 1 mean neurologic severity score, control = 22 ± 3 vs. VPA 150 mg/kg = 8 ± 7 or VPA 50 mg/kg = 6 ± 6; p = 0.02 and 0.003). Valproic acid-treated animals had significantly smaller brain lesion sizes (mean volume in mm3, control = 1,268.0 ± 241.2 vs. VPA 150 mg/kg = 620.4 ± 328.0 or VPA 50 mg/kg = 438.6 ± 234.8; p = 0.007 and 0.001). CONCLUSION: In swine subjected to TBI and hemorrhagic shock, VPA treatment, in a dose that is approved for clinical use, decreases brain lesion size and reduces neurologic impairment compared with resuscitation alone.
Asunto(s)
Lesiones Traumáticas del Encéfalo , Enfermedades del Sistema Nervioso , Choque Hemorrágico , Ácido Valproico/farmacología , Animales , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/diagnóstico , Lesiones Traumáticas del Encéfalo/fisiopatología , Lesiones Traumáticas del Encéfalo/terapia , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Monitoreo de Drogas , Inhibidores de Histona Desacetilasas/farmacología , Imagen por Resonancia Magnética , Enfermedades del Sistema Nervioso/diagnóstico , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Enfermedades del Sistema Nervioso/etiología , Examen Neurológico , Choque Hemorrágico/diagnóstico , Choque Hemorrágico/etiología , Choque Hemorrágico/terapia , Porcinos , Índices de Gravedad del Trauma , Resultado del TratamientoRESUMEN
BACKGROUND: Early single-dose treatment with human mesenchymal stem cell-derived exosomes promotes neuroprotection and promotes blood-brain barrier integrity in models of traumatic brain injury (TBI) and hemorrhagic shock (HS) in swine. The impact of an early single dose of exosomes on late survival (7 days), however, remains unknown. We sought to evaluate the impact of early single-dose exosome treatment on neurologic outcomes, brain lesion size, inflammatory cytokines, apoptotic markers, and mediators of neural plasticity in a 7-day survival model. METHODS: Yorkshire swine were subjected to a severe TBI (8-mm cortical impact) and HS (40% estimated total blood volume). After 1 hour of shock, animals were randomized (n = 4/cohort) to receive either lactated Ringer's (5 mL) or lactated Ringer's with exosomes (1 × 10 exosome particles). After an additional hour of shock, animals were resuscitated with normal saline. Daily neurologic severity scores were compared. At 7 days following injury, lesion size, inflammatory markers, and mediators of inflammation (NF-κB), apoptosis (BAX), and neural plasticity (brain-derived neurotrophic factor) in brain tissue were compared between groups. RESULTS: Exosome-treated animals had significantly lower neurologic severity scores (first 4 days; p < 0.05) and faster neurologic recovery. At 7 days, exosome-treated animals had significantly smaller (p < 0.05) brain lesion sizes. Exosome-treated animals also had significantly lower levels of inflammatory markers (interleukin [IL]-1, IL-6, IL-8, and IL-18) and higher granulocyte-macrophage colony-stimulating factor levels compared with the control animals, indicating specific impacts on various cytokines. The BAX and NF-κB levels were significantly lower (p < 0.05) in exosome-treated animals, while brain-derived neurotrophic factor levels were significantly higher (p < 0.05) in the exosome-treated animals. CONCLUSION: In a large animal model of TBI and HS, early single-dose exosome treatment attenuates neurologic injury, decreases brain lesion size, inhibits inflammation and apoptosis, and promotes neural plasticity over a 7-day period.
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Lesiones Traumáticas del Encéfalo/fisiopatología , Lesiones Traumáticas del Encéfalo/terapia , Exosomas , Neuroprotección , Choque Hemorrágico/fisiopatología , Choque Hemorrágico/terapia , Animales , Apoptosis , Barrera Hematoencefálica , Lesiones Traumáticas del Encéfalo/patología , Citocinas/sangre , Modelos Animales de Enfermedad , Femenino , Hemodinámica , Inflamación/patología , Células Madre Mesenquimatosas/citología , FN-kappa B/sangre , Choque Hemorrágico/patología , Transducción de Señal , Porcinos , Resultado del Tratamiento , Proteína X Asociada a bcl-2/sangreRESUMEN
BACKGROUND: Although damage control resuscitation (DCR) is routinely performed for short durations, prolonged DCR may be required in military conflicts as a component of prolonged field care. Valproic acid (VPA) has been shown to have beneficial properties in lethal hemorrhage/trauma models. We sought to investigate whether the addition of a single dose of VPA to a 72-hour prolonged DCR protocol would improve clinical outcomes. METHODS: Fifteen Yorkshire swine (40-45 kg) were subjected to lethal (50% estimated total blood volume) hemorrhagic shock (HS) and randomized to three groups: (1) HS, (2) HS-DCR, (3) HS-DCR-VPA (150 mg/kg over 3 hours) (n = 5/cohort). In groups assigned to receive DCR, Tactical Combat Casualty Care guidelines were applied (1 hour into the shock period), targeting a systolic blood pressure of 80 mm Hg. At 72 hours, surviving animals were given transfusion of packed red blood cells, simulating evacuation to higher echelons of care. Survival rates, physiologic parameters, resuscitative fluid requirements, and laboratory profiles were used to compare the clinical outcomes. RESULTS: This model was 100% lethal in the untreated animals. DCR improved survival to 20%, although this was not statistically significant. The addition of VPA to DCR significantly improved survival to 80% (p < 0.01). The VPA-treated animals also had significantly (p < 0.05) higher systolic blood pressures, lower fluid resuscitation requirements, higher hemoglobin levels, and lower creatinine and potassium levels. CONCLUSION: VPA administration improves survival, decreases resuscitation requirements, and improves hemodynamic and laboratory parameters when added to prolonged DCR in a lethal hemorrhage model.