In-depth characterization of a long-term, resuscitated model of acute subdural hematoma–induced brain injury

Abstract

<jats:sec><jats:title>OBJECTIVE</jats:title><jats:p>Acute subdural hematoma (ASDH) is a leading entity in brain injury. Rodent models mostly lack standard intensive care, while large animal models frequently are only short term. Therefore, the authors developed a long-term, resuscitated porcine model of ASDH-induced brain injury and report their findings.</jats:p></jats:sec><jats:sec><jats:title>METHODS</jats:title><jats:p>Anesthetized, mechanically ventilated, and instrumented pigs with human-like coagulation underwent subdural injection of 20 mL of autologous blood and subsequent observation for 54 hours. Continuous bilateral multimodal brain monitoring (intracranial pressure [ICP], cerebral perfusion pressure [CPP], partial pressure of oxygen in brain tissue [PbtO<jats:sub>2</jats:sub>], and brain temperature) was combined with intermittent neurological assessment (veterinary modified Glasgow Coma Scale [MGCS]), microdialysis, and measurement of plasma protein S100β, GFAP, neuron-specific enolase [NSE], nitrite+nitrate, and isoprostanes. Fluid resuscitation and continuous intravenous norepinephrine were targeted to maintain CPP at pre-ASDH levels. Immediately postmortem, the brains were taken for macroscopic and histological evaluation, immunohistochemical analysis for nitrotyrosine formation, albumin extravasation, NADPH oxidase 2 (NOX2) and GFAP expression, and quantification of tissue mitochondrial respiration.</jats:p></jats:sec><jats:sec><jats:title>RESULTS</jats:title><jats:p>Nine of 11 pigs survived the complete observation period. While ICP significantly increased after ASDH induction, CPP, PbtO<jats:sub>2</jats:sub>, and the MGCS score remained unaffected. Blood S100β levels significantly fell over time, whereas GFAP, NSE, nitrite+nitrate, and isoprostane concentrations were unaltered. Immunohistochemistry showed nitrotyrosine formation, albumin extravasation, NOX2 expression, fibrillary astrogliosis, and microglial activation.</jats:p></jats:sec><jats:sec><jats:title>CONCLUSIONS</jats:title><jats:p>The authors describe a clinically relevant, long-term, resuscitated porcine model of ASDH-induced brain injury. Despite the morphological injury, maintaining CPP and PbtO<jats:sub>2</jats:sub> prevented serious neurological dysfunction. This model is suitable for studying therapeutic interventions during hemorrhage-induced acute brain injury with standard brain-targeted intensive care.</jats:p></jats:sec>

Cerebral Immunohistochemical Characterization of the H2S and the Oxytocin Systems in a Porcine Model of Acute Subdural Hematoma

“…1316, date of approval June 20, 2016). All experiments were conducted in adherence with the National Institute of Health Guidelines on the Use of Laboratory Animals and the European Union “Directive 2010/63/EU on the protection of animals used for scientific purposes.” This is an immunohistochemical study performed on available brain sections from a recently published porcine model of ASDH ( 1 ): 5 female and 4 male (castrated) anesthetized Bretoncelles-Meishan-Willebrand pigs (age 11 months, 65 kg). IHC allowed us to study and visualize the nuclear or cytoplasmic protein localization in the global landscape of the brain.…”

“…Anesthesia, surgical procedures and resuscitation were described in detail previously ( 1 ) ASDH was induced by injection of 20 mL of autologous blood via a subdural catheter above the left parietal cortex. Therefore, the skull was exposed and a craniotomy was performed by drilling a hole over the left and right parietal cortex and a small incision of the dura was made.…”

“…According to the 3R principle the right hemisphere was also instrumented to avoid the need for additional sham experiments. Microdialysis catheters and multimodal brain monitoring probes were inserted in both hemispheres of brain parenchyma ( 1 ).…”

“…Recently we described a long-term (54 h) resuscitated porcine model of acute subdural hematoma (ASDH)-induced acute brain injury, which comprised elevated intracranial pressure (ICP), and morphological damage without major neurological dysfunction, due to the neuro-intensive care maintenance of cerebral perfusion pressure (CPP) and tissue oxygen (PbtO 2 ) ( 1 ).…”

“…Therefore, the aim of the present study is to further characterize, immunohistochemically, the spatial protein expression of OTR, OT and the H 2 S producing enzymes and assessing potential mediators for porcine acute brain injury in the available material from our ASDH pilot study ( 1 ).…”